Imidazopyridine compound

ABSTRACT

A compound represented by the following general formula (1), or a salt or hydrate thereof:  
                 
 
wherein R 1  represents a C1-C6 alkyl group or C2-C6 alkynyl group which may be substituted, or a phenyl group which may be substituted, R 2  represents a hydrogen atom or a C1-C6 alkyl group, R 3  represents methyl or ethyl group, R 4  represents a C1-C6 alkyl group, R 5  represents a hydrogen atom, provided that a compound wherein R 1  is a C1-C6 alkyl group unsubstituted or substituted with a halogen atom and R 2  is a hydrogen atom is excluded.

TECHNICAL FIELD

The present invention relates to an imidazopyridine compound useful as agastric acid secretion inhibitor, or a salt thereof or a hydratethereof.

The present invention also relates to an imidazopyridine compound usefulas a therapeutic or preventive agent for acid related diseases(especially gastroesophageal reflux disease, symptomaticgastroesophageal reflux disease, gastric ulcer or duodenal ulcer), or asalt thereof or a hydrate thereof.

BACKGROUND ART

Peptic ulcer, such as gastric ulcer and duodenal ulcer, is considered tohave developed as a result of self-digestion caused by imbalance betweenaggressive factors, such as acid and pepsin, and protective factors,such as mucus and blood.

The treatment of peptic ulcer is carried out by internal medicine inprinciple, and various drug treatments have been attempted.Particularly, drugs specifically inhibiting H⁺-, K⁺-ATPase, an enzymepresent in gastric parietal cells and in charge of the final step ofgastric acid secretion, suppressing the acid secretion and therebypreventing self-digestion, for example, omeprazole, esomeprazole,pantoprazole, lansoprazole, rabeprazole, etc., have been recentlydeveloped and clinically used.

Although these drugs have excellent therapeutic effects, drugs whichhave more long-lasting inhibitory effect on gastric acid secretion,higher safety and more suitable physicochemical stability are furtherrequired.

Compounds especially relevant to the present invention are described inthe patent documents 1 to 3 but the specific compounds described inthese patent documents and the specific compounds of the presentinvention are different in the chemical structure.

-   -   Patent Document 1 JP-A-62-207271    -   Patent Document 2 EP-A-0254588    -   Patent Document 3 EP-A-0187977

DISCLOSURE OF THE INVENTION

Problems to be Solved by the Invention

An object of the present invention is to provide a new compound havingan excellent inhibitory effect on gastric acid secretion which is usefulas a therapeutic or preventive agent for the treatment of acid relateddiseases.

Measures for Solving the Problems

The present inventors have conducted intensive studies for solving theabove described problems, and as a result, have found that animidazopyridine compound having a novel chemical structure has anexcellent inhibition effect on gastric acid secretion and is useful as atherapeutic or preventive agent particularly for gastroesophageal refluxdisease, symptomatic gastroesophageal reflux disease, gastric ulcer orduodenal ulcer, and thus completed the present invention.

That is, the present invention is directed to a compound having thefollowing general formula (1), or a salt thereof or a hydrate thereof.

The present invention is also directed to a drug comprising the compoundhaving the above described general formula (1), or a salt thereof or ahydrate thereof and a pharmaceutically acceptable carrier.

The present invention is further directed to a gastric acid secretioninhibitor comprising a compound having the above described generalformula (1), or a salt thereof or a hydrate thereof.

The present invention is still further directed to a method using acompound of formula (1), or a therapeutic or preventive agent comprisinga compound having the above described general formula (1), or a saltthereof or a hydrate thereof, for diseases caused by gastric acid,specifically, gastric ulcer, duodenal ulcer, stomal ulcer,gastroesophageal reflux disease, Zollinger-Ellison syndrome, symptomaticgastroesophageal reflux disease, endoscopy-negative gastroesophagealreflux disease, gastroesophageal regurgitation, paresthesia ofpharyngolarynx, Barrett's esophagus, non-steroidal antiinflammatory drug(NSAID) ulcer, gastritis, stomach bleeding, gastrointestinal bleeding,peptic ulcer, bleeding ulcer, stress ulcer, gastric hyperacidity,dyspepsia, gastraparesis, senile ulcer, intractable ulcer, heartburn,bruxism, stomachache, heavy stomach, temporomandibular arthrosis orerosive gastritis. The method involves administering an effective amountof the compound or composition to a patient in need thereof.

Suitable examples of “acid related diseases” include, for example,gastric ulcer, duodenal ulcer, stomal ulcer, gastroesophageal refluxdisease, Zollinger-Ellison syndrome or symptomatic gastroesophagealreflux disease, and more suitable examples include gastroesophagealreflux disease, symptomatic gastroesophageal reflux disease, gastriculcer or duodenal ulcer, and still more suitable examples include (1)gastroesophageal reflux disease or symptomatic gastroesophageal refluxdisease, or (2) gastric ulcers or duodenal ulcer.

In the meantime, the present invention is directed to a mono therapeuticor combination therapeutic agent for the eradication of HelicobacterPylori comprising a compound having the above described general formula(1), or a salt thereof or a hydrate thereof.

Here, the above mentioned “preventive agent” includes an agentadministered before onset of the disease, as well as a maintenancetherapy agent or a relapse preventing agent after the disease is cured.

Further, the above mentioned “combination therapeutic agent for theeradication of Helicobacter Pylori” means a drug suitably adjusting theenvironment so that an eradicating agent, which is difficult to exhibitthe effect under acidic condition, can exhibit its effect.

In the above described formula (1),

-   -   R¹ represents a C1-C6 alkyl group which may have at least one        substituent selected from the following α group, a C2-C6 alkenyl        group, a C2-C6 alkynyl group, a C3-C6 cycloalkyl group, or a        phenyl group which may have a substituent selected from the        following β group;    -   R² represents a hydrogen atom or a C1-C3 alkyl group;    -   R³ represents methyl or ethyl group;    -   R⁴ represents a C1-C6 alkyl group;    -   R⁵ represents a hydrogen atom;    -   α group represents a group consisting of a halogen atom, a C3-C6        cycloalkyl group, a phenyl group which may have at least one        substituent selected from the following β group and a phenyloxy        group which may have a substituent selected from the following β        group;    -   β group represents a group consisting of a halogen atom and a        C1-C6 alkoxy group;    -   provided that a compound wherein R¹ is a C1-C6 alkyl group        unsubstituted or substituted with a halogen atom and R² is a        hydrogen atom, or a salt thereof or a hydrate thereof are        excluded from the present invention.

A “C1-C6 alkyl group” as used in this specification for convenience sakemeans a straight chain or branched chain alkyl group having 1 to 6carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, s-butyl, t-butyl, pentyl, isopentyl, 2-methylbutyl, neopentyl,1-ethylpropyl, hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl,2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl,1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl,2,3-dimethylbutyl, 1-ethylbutyl or 2-ethylbutyl group.

A “C1-C3 alkyl group” as used in this specification for convenience sakemeans a straight chain or branched chain alkyl group having 1 to 3carbon atoms such as methyl, ethyl, n-propyl or isopropyl.

A “C2-6 alkenyl group” as used in this specification for conveniencesake means a vinyl group, allyl group, 1-propenyl group, isopropenylgroup, 1-butenyl group, 2-butenyl group, 3-butenyl group,1,3-pentadienyl group or 1,4-hexadienyl group.

A “C2-C6 alkynyl group” as used in this specification for conveniencesake means an alkynyl group having 2 to 6 carbon atoms and 1 to 2 triplebonds such as ethynyl group, 1-propynyl group, 2-propynyl group,2-butynyl group, 3-butynyl group, 1,3-pentadiynyl group, 1,4-hexadiynylgroup, pentynyl group, or hexynyl group.

A “C3-6 cycloalkyl group” as used in this specification for conveniencesake means a cyclopropyl group, cyclobutyl group, cyclopentyl group orcyclohexyl group.

A “halogen atom” as used in this specification for convenience sakemeans a fluorine atom, a chlorine atom, a bromine atom or an iodineatom.

A “C1-C6 alkoxy group” as used in this specification for conveniencesake means a straight chain or branched chain alkoxy group having 1 to 6carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, butoxy,isobutoxy, s-butoxy, t-butoxy, pentoxy, isopentoxy, 2-methylbutoxy,neopentoxy, hexyloxy, 4-methylpentoxy, 3-methylpentoxy, 2-methylpentoxy,3,3-dimethylbutoxy, 2,2-dimethylbutoxy, 1,1-dimethylbutoxy,1,2-dimethylbutoxy, 1,3-dimethylbutoxy or 2,3-dimethylbutoxy group.

The expressions “which may be substituted” or “which may have at leastone substituent” as used in this specification for convenience sake havethe same meaning as “which may have one to three substituents atsubstitutable position(s) in any combination” unless the number of thesubstituent is particularly specified.

The expression “which is (are) substituted” as used in thisspecification for convenience sake has the same meaning as “which has(have) one to three substituents at substitutable position(s) in anycombination” unless the number of the substituent(s) is particularlyspecified.

Preferably the above mentioned R¹ is an unsubstituted C1-C6 alkyl group,a C2-C6 alkynyl group or a C1-C6 alkyl group which may be substitutedwith halogen or a phenyl group which may have a substituent selectedfrom the above described β group, and more preferably methyl group,2,2,2-trifluoroethyl group, 2,2-difluoroethyl group, 2-(phenyl)propylgroup, 2-(phenyloxy)ethyl group, 2-butynyl group, 3-fluorophenyl group,4-fluorophenyl group or 4-methoxyphenyl group, and more preferablymethyl group, 2,2,2-trifluoroethyl group or 2,2-difluoroethyl group, andmost preferably methyl group.

Preferably, the above mentioned R² is a hydrogen atom, methyl group,ethyl group, or propyl group, and more preferably a hydrogen atom ormethyl group.

The above mentioned R³ is preferably a methyl group.

The above mentioned R⁴ is preferably a methyl group.

Although the structural formula of a compound may represent a particularisomer in this specification for convenience sake, the present inventionencompasses all the isomers including geometric isomers, opticalisomers, stereoisomers and tautomer, and mixtures of isomers generatedby the structure of the compound, and the compound is not limited to theparticular formula described for convenience sake and may be either oneof the isomer or a mixtures of isomers. Therefore, the compound of thepresent invention, which may be an optically active object and racemate,is not limited to a particular one and may include either one.Similarly, crystal polymorphism which may exist is not limited, and thecrystal may comprise a single crystal form or may be a mixture, and thecompound of the present invention may include an anhydride as well as ahydrate. Furthermore, so-called metabolite which is generated by thedecomposition of Compound (1) of the present invention in a living bodyis also included by the present invention. Furthermore, the compound(so-called prodrug) which will lead to Compound (1) of the presentinvention through metabolism such as oxidization, reduction, hydrolysisand conjugation in a living body is also included by the presentinvention.

The compound of the present invention forms a salt in the abovedescribed general formula (1) at 1- or 3-position NH group in theimidazopyridine skeleton.

The “salt” is not particularly limited as long without any treatment ispharmacologically acceptable, and includes, for example, an inorganicbase salt or an organic base salt.

Preferable examples of inorganic base salt include alkaline metal saltssuch as sodium salt and potassium salt, alkaline-earth-metals salts suchas calcium salt or magnesium salt, aluminum salt or ammonium salt, andpreferable examples of organic base salt include diethylamine salt,diethanolamine salt, meglumine salt or N,N′-dibenzylethylenediaminesalt, etc.

Preferable compounds of the general formula

-   (1) of the present invention include:-   (2) compounds in which R¹ is an unsubstituted C1-C6 alkyl group, or    a salt thereof or a hydrate thereof,-   (3) compounds in which R¹ is a C2-C6 alkynyl group, or a salt    thereof or a hydrate thereof,-   (4) compounds in which R¹ is a C1-C6 alkyl group which may be    substituted with halogen, or a salt thereof or a hydrate thereof,-   (5) compounds in which R¹ is a phenyl group which may have a    substituent selected from the above described β group, or a salt    thereof or a hydrate thereof,-   (6) compounds in which R¹ is methyl group, 2,2,2-trifluoroethyl    group, 2,2-difluoroethyl group, 2-(phenyl)propyl group,    2-(phenyloxy)ethyl group, 2-butynyl group, 3-fluorophenyl group,    4-fluorophenyl group or 4-methoxyphenyl group, or a salt thereof or    a hydrate thereof,-   (7) compounds in which R¹ is methyl group, 2,2,2-trifluoroethyl    group or 2,2-difluoroethyl group, or a salt thereof or a hydrate    thereof,-   (8) compounds in which R² is a hydrogen atom, methyl group, ethyl    group, or a propyl group, or a salt thereof or a hydrate thereof,-   (9) compounds in which R² is methyl group, or a salt thereof or a    hydrate thereof,-   (10) compounds in which R² is a hydrogen atom, or a salt thereof or    a hydrate thereof,-   (11) compounds in which R³ is methyl group, or a salt thereof or a    hydrate thereof, or-   (12) compounds in which R⁴ is methyl group, or a salt thereof or a    hydrate thereof.

Furthermore, compounds obtained by selecting R¹ from the above (2), (3),(4), (5), (6) or (7), R² from the above (8), (9) or (10),

R³ from the above (11) or R⁴ from the above (12) in any combination, ora salt thereof or a hydrate thereof are also preferable.

Preferable compounds among the specific compounds of the presentinvention, or a salt thereof or a hydrate thereof are5-methoxy-2-(((4-methoxy-3-methyl-2-pyridinyl)methyl)sulfinyl)-6-methyl-3H-imidazo[4,5-b]pyridine,2-(((4-methoxy-3-methyl-2-pyridinyl)methyl)sulfinyl)-6-methyl-5-(2,2,2-trifluoroethoxy)-3H-imidazo[4,5-b]pyridine,or5-(2,2-difluoroethoxy)-2-(((4-methoxy-3-methyl-2-pyridinyl)methyl)sulfinyl)-6-methyl-3H-imidazo[4,5-b]pyridine,or a salt thereof or a hydrate thereof (especially a sodium saltthereof).

EFFECT OF THE INVENTION

Since the compound of the present invention has excellent gastric acidsecretion inhibitory activity, more sustainable gastric acid secretioninhibitory activity, higher safety (for example, causing less inductionof cytochrome P450) and more suitable physicochemical stability, it isuseful as a pharmaceutical agent, particularly a therapeutic orpreventive agent for acid related diseases and a mono therapeutic orcombination therapeutic agent for the eradication of HelicobacterPylori.

BEST MODE FOR CARRYING OUT THE INVENTION

The compound of the present invention can be produced by the processindicated below. However, process for producing the compound the presentinvention is not limited thereto.

Compound (1) of the present invention can be produced by the followingProcess A.

In the above scheme, R¹, R², R³, R⁴ and R⁵ represent the same as definedabove, and X¹ represents a leaving group and is preferably analkylsulfonyloxy group which may be substituted or a benzenesulfonyloxygroup which may be substituted (for example, methanesulfonyloxy,ethanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy group, etc.)or a chlorine atom, a bromine atom or an iodine atom, and morepreferably a chlorine atom and a methanesulfonyloxy group.

Hereafter, each step of Process A method is explained.

(Step A-1) Thioetherification

This step is a step where Compound (2) and Compound (3) or a saltthereof (particularly, a hydrochloride salt) is made to react in thepresence or absence of a base, in the absence of a solvent or in aninert solvent to produce Compound (4).

As Compound (4a), a commercially available compound or a compoundsynthesized based on a process known by publication can be used.

The usable solvent is not particularly limited as long as it candissolve the starting materials to some extent and does not inhibit thereaction, and includes, for example, alcohols such as methanol, ethanol,n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamylalcohol, diethylene glycol, glycerin, octanol, cyclohexanol and methylcellosolve; halogenated hydrocarbons such as chloroform,dichloromethane, 1,2-dichloroethane and carbon tetrachloride; etherssuch as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane,dimethoxyethane, diethylene glycol dimethyl ether;N,N-dimethylformamide; dimethylsulfoxide; water; or mixtures of thesesolvents, and is preferably alcohols and most preferably methanol.

The usable base includes, for example, inorganic bases such as sodiumhydride, potassium hydride, lithium carbonate, sodium carbonate,potassium carbonate, lithium hydroxide, sodium hydroxide, potassiumhydroxide; and organic bases such as N-methylmorpholine, triethylamine,tripropylamine, tributylamine, diisopropylethylamine, dicyclohexylamine,N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline,4-(N,N-dimethylamino)pyridine, 2,6-di(t-butyl)-4-methylpyridine,quinoline, N,N-dimethyl aniline, N,N-diethylaniline,1,5-diazabicyclo[4.3.0]nona-5-ene (DBN), 1,4-diazabicyclo[2.2.2]octane(DABCO), 1,8-diazabicyclo[5.4.0]undeca-7-ene (DBU), and is preferablyinorganic bases such as sodium hydride, potassium hydride, lithiumhydroxide, sodium hydroxide, potassium hydroxide, and most preferablysodium hydroxide.

Although the reaction temperature may vary depending on startingmaterials, solvent and base catalyst, it is typically 0 to 100° C., andis preferably 10 to 40° C.

Although the reaction time may vary depending on starting materials,solvent, base catalyst and reaction temperature, it is typically 30minutes to 20 hours, and is preferably 1 to 8 hours.

(Step A-2) Oxidation Reaction

This step is a step where an oxidizing reagent is made to react withCompound (4) in the absence of a solvent or in an inert solvent toproduce Compound (1) of the present invention.

The usable solvent is not particularly limited as long as it candissolve the starting materials to some extent and does not inhibit thereaction, and includes, for example, alcohols such as methanol, ethanol,n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamylalcohol, diethylene glycol, glycerin, octanol, cyclohexanol and methylcellosolve; aromatic hydrocarbons such as benzene, toluene; halogenatedhydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane andcarbon tetrachloride; amides such as formamide, N,N-dimethylformamide,N,N-dimethylacetamide, hexamethylphosphoric triamide, and is preferablyan aromatic hydrocarbon, an alcohol or a mixture of these solvents, andmost preferably is a mixture of toluene and methanol, ordichloromethane.

The usable oxidizing reagent includes, for example, aqueous hydrogenperoxide solution, t-butyl hydroperoxide, sodium periodate, peraceticacid, perbenzoic acid, metachloroperbenzoic acid, urea-hydrogen peroxideaddition compound ((NH₂)₂CO.H₂O₂), etc., and it is preferablymetachloroperbenzoic acid. When performing asymmetric oxidation, acommonly used asymmetric oxidizing agent can also be used.

Although the reaction temperature may vary depending on startingmaterials, solvent, and oxidizing reagents, typically, it is −100 to100° C., and preferably −70 to 70° C.

Although the reaction time may vary depending on starting materials,solvent, oxidizing reagent and reaction temperature, it is typically 30minutes to 24 hours, and is preferably 1 to 5 hours.

The compound obtained above can be converted to a salt by an ordinarymethod. For example, a base is made to react with Compound (1) in theabsence of a solvent or in an inert solvent. An alcohol such as methanolor ethanol, water or a mixture of these solvents, preferably a mixtureof ethanol and water is used as a solvent, and an alkaline metalhydroxide such as sodium hydroxide and potassium hydroxide, analkaline-earth-metals hydroxide such as magnesium hydroxide, an alkoxidesuch as sodium methoxide, sodium t-butoxide and magnesium methoxide,preferably sodium hydroxide, is used as a base in an aqueous solution.Typically, the reaction temperature is −50 to 50° C., and is preferably10 to 40° C. Typically, the reaction time is 5 minutes to 2 hours, andis preferably 10 to 30 minutes.

Compound (2) and compound (3) which are intermediates in the abovedescribed Process A may be commercial products or easily produced fromcommercial products by a process which those skilled in the art usuallyemploys, and they can also be produced by Processes B, C, D or Edescribed below.

Compound (2) can be produced by the following Process B.

In the above scheme, R¹ and R² represent the same as defined above, andR^(2a) represents a methyl group, vinyl group or allyl group, and X²represents a leaving group, preferably a chlorine atom, a bromine atomor an iodine atom, and more preferably a chlorine atom. X³ represents aleaving group, preferably a chlorine atom, a bromine atom or an iodineatom, and more preferably an iodine atom.

Hereafter, each step of the Process B is explained.

(Step B-1) Amination Reaction

This step is a step where ammonia is made to react with Compound (4) inthe presence or absence of an alkaline metal carbonate, in the absenceof a solvent or in an inert solvent, to produce Compound (5).

The usable solvent is not particularly limited as long as it candissolve the starting materials to some extent and does not inhibit thereaction, and includes, for example, aliphatic hydrocarbons such ashexane, heptane, ligroin, petroleum ether; halogenated hydrocarbons suchas chloroform, dichloromethane, 1,2-dichloroethane, carbontetrachloride; ethers such as diethyl ether, diisopropyl ether,tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethylether; amides such as formamide, N,N-dimethylformamide,N,N-dimethylacetamide, hexamethylphosphoric triamide; t-butyl alcohol,water, etc., and is preferably a mixture of t-butyl alcohol and water ora mixture of N,N-dimethylformamide and water.

The usable alkaline metal carbonate includes, for example, sodiumcarbonate, potassium carbonate, sodium bicarbonate, potassiumbicarbonate, etc., and is preferably potassium carbonate.

Although the reaction temperature may vary depending on startingmaterials, solvent, and alkaline metal carbonate, it is typically 0 to100° C., and is preferably 40 to 80° C.

Although the reaction time may vary depending on starting materials,solvent, alkaline metal carbonate, and reaction temperature, it istypically 6 to 48 hours and is preferably 12 to 36 hours.

As Compound (4), a commercially available compound or a compoundsynthesized according to any process known by publication can be used.

(Step B-2) R¹—O Group Introducing Reaction

Reaction conditions may be changed depending on the type of R¹—OH.

a) In the Case that R¹—OH is an Alcohol:

This step is a step where Compound (5) and alcohol R¹—OH (wherein R¹represent the same as defined above) are made to react in the presenceof a base in the absence of a solvent or in an inert solvent to produceCompound (6).

The usable solvent is not particularly limited as long as it candissolve the starting materials to some extent and does not inhibit thereaction, and includes, for example, alcohols which form the desiredR¹—O— such as methanol and ethanol; aliphatic hydrocarbons such ashexane, heptane, ligroin, petroleum ether; halogenated hydrocarbons suchas chloroform, dichloromethane, 1,2-dichloroethane, carbontetrachloride; aromatic hydrocarbons such as benzene, toluene; etherssuch as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane,dimethoxyethane, diethylene glycol dimethyl ether; amides such asformamide, N,N-dimethylformamide, N,N-dimethylacetamide,hexamethylphosphoric triamide, N-methylpyrrolidone; dimethylsulfoxide,water, or a mixture of these solvents, and is preferablydimethylsulfoxide, ether or amide, and most preferably, tetrahydrofuranwhen R¹—OH is primary alcohol, and dimethylsulfoxide orN-methylpyrrolidone in the case of secondary alcohol.

The usable base includes, for example, alkaline metal carbonates such aslithium carbonate, sodium carbonate, potassium carbonate; alkaline metalhydroxides such as lithium hydroxide, sodium hydroxide, potassiumhydroxide; metal alkoxides such as lithium methoxide, sodium methoxide,sodium ethoxide, potassium-t-butoxide; alkaline metal hydrides such assodium hydride, potassium hydride; alkaline metal alkoxides preparedfrom alkaline metals; n-butyl lithium, lithium diisopropylamide, etc.,and it is preferably an alkaline metal hydride and most preferablysodium hydride.

Although the reaction temperature may vary depending on startingmaterials, solvent, and bases, it is typically 0 to 100° C., and whenR¹—OH is a primary alcohol, it is 10 to 40° C., and in the case ofsecondary alcohol, it is 50 to 100° C.

Although the reaction time may vary depending on starting materials,solvent, base, and reaction temperature, it is typically 6 to 48 hoursand is preferably 12 to 24 hours.

b) In the Case that R¹—OH is a Phenol

This step is a step where Compound (5) and a phenol R¹—OH (wherein R¹represent the same as defined above) are made to react in the presenceof a palladium catalyst, ligand, and an alkaline metal phosphate in theabsence of a solvent or in an inert solvent to produce Compound (6).

The usable solvent is not particularly limited as long as it candissolve the starting materials to some extent and does not inhibit thereaction, and includes, for example, alcohols such as methanol, ethanol,n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamylalcohol, diethylene glycol, glycerin, octanol, cyclohexanol and methylcellosolve; aliphatic hydrocarbons such as hexane, heptane, ligroin,petroleum ether; ethers such as diethyl ether, tetrahydrofuran, dioxane,dimethoxyethane, diethylene glycol dimethyl ether; halogenatedhydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane andcarbon tetrachloride; aromatic hydrocarbons such as benzene, toluene;amides such as formamide, N,N-dimethylformamide, N,N-dimethylacetamide,hexamethylphosphoric triamide; organic acids such as acetic acid, etc.,and is preferably an aromatic hydrocarbon and most preferably toluene.

The usable palladium catalyst includes, for example, a palladiumcatalyst such as tetrakis(triphenylphosphine)palladium(0),tris(dibenzylideneacetone)dipalladium(0),bis(dibenzylideneacetone)palladium(0),bis(tri-t-butylphosphine)palladium(0), palladium black; a palladiumcatalyst precursor (which generates a palladium catalyst within asystem) such as dichlorobis(triphenylphosphine)palladium(II),palladium(II) acetate,1,1′-bis(diphenylphosphino)ferrocenedichloropalladium(II),dichlorobis(tri-o-tolylphosphine)palladium(II),dichlorobis(tricyclohexylphosphine)palladium(II) etc., and is preferablypalladium(II) acetate.

The usable ligand includes, for example, triphenylphosphine,tri-t-butylphosphine, tri(4-methylphenyl)phosphine,2-(di-t-butylphosphino)biphenyl, 2-(dicyclohexylphosphino)biphenyl,tricyclohexylphosphine, 1,1′-bis(diphenylphosphino)ferrocene,di-t-butylphosphoniumtetrafluoroborate, etc., and is preferably2-(di-t-butylphosphino)biphenyl.

The usable alkaline metal phosphate includes, for example, sodiumphosphate, potassium phosphate, etc., and is preferably potassiumphosphate.

Although the reaction temperature may vary depending on startingmaterials, solvent, palladium catalysts, etc., it is typically 50 to200° C., and preferably 120 to 180° C.

Although the reaction time may vary depending on starting materials,solvent, palladium catalyst, reaction temperature, etc., it is typically6 to 48 hours and is preferably 12 to 24 hours.

(Step B-3) Halogenation Reaction (Represented by Bromination and anIodization Reaction)

This step is a step where a brominating agent or an iodizing agent ismade to react with Compound (6) in the absence of a solvent or in aninert solvent to produce Compound (7).

The usable solvent is not particularly limited as long as it candissolve the starting materials to some extent and does not inhibit thereaction, and includes, for example, alcohols such as methanol, ethanol,n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamylalcohol, diethylene glycol, glycerin, octanol, cyclohexanol, methylcellosolve; aliphatic hydrocarbons such as hexane, heptane, ligroin,petroleum ether; halogenated hydrocarbons such as chloroform,dichloromethane, 1,2-dichloroethane and carbon tetrachloride; etherssuch as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane,dimethoxyethane, diethylene glycol dimethyl ether; nitrile such asacetonitrile; amides such as formamide, N,N-dimethylformamide,N,N-dimethylacetamide and hexamethylphosphoric triamide; organic acidssuch as acetic acid, etc., and it is preferably acetonitrile, an alcohol(particularly methanol) or an organic acid and most preferably aceticacid or acetonitrile.

The usable brominating or iodizing agent includes, for example, bromine(Br₂), iodine (I₂), N-bromosuccinimide, N-iodosuccinimide, etc., and ispreferably N-iodosuccinimide or N-bromosuccinimide.

Although the reaction temperature may vary depending on startingmaterials, solvent, brominating or iodizing agent, it is typically 0 to60° C., and preferably 10 to 40° C.

Although the reaction time may vary depending on starting materials,solvent, brominating agent or iodizing agent, reaction temperature,etc., it is typically 2 to 24 hours and preferably 5 to 24 hours.

(Step B-4) Alkylation or Alkenylation Reaction

(1) In the Case that R^(2a) is Methyl Group

This step is a step where Compound (7) and a desired trialkylboroxin aremade to react in the presence of a palladium catalyst and a base in theabsence of a solvent or in an inert solvent to produce Compound (8).

The usable solvent is not particularly limited as long as it candissolve the starting materials to some extent and does not inhibit thereaction, and includes, for example, aromatic hydrocarbons such asbenzene, toluene, xylene; ethers such as dioxane, dimethoxyethane,tetrahydrofuran; amides such as N,N-dimethylformamide, and it ispreferably tetrahydrofuran or N,N-dimethylformamide.

The usable palladium catalyst includes, for example, a palladiumcatalyst such as dichlorobis(triphenylphosphine)palladium(II),tetrakis(triphenylphosphine)palladium(0),tris(dibenzylideneacetone)dipalladium(0),bis(dibenzylideneacetone)palladium(0),bis(tri-t-butylphosphine)palladium(0), palladium black, etc., andpreferably dichlorobis(triphenylphosphine)palladium(II) ortetrakis(triphenylphosphine)palladium(0).

The usable base includes, for example, bases such as potassiumt-butoxide, sodium t-butoxide, cesium carbonate, and preferably cesiumcarbonate.

Although the reaction temperature may vary depending on startingmaterials, solvent, palladium catalysts, etc., it is typically 50 to200° C., and preferably 70 to 150° C.

Although the reaction time may vary depending on starting materials,solvent, palladium catalyst, reaction temperature, etc., it is typically30 minutes to 48 hours, and preferably 5 to 12 hours.

(2) In the Case that R^(2a) is Vinyl or Allyl Group

This step is a step where Compound (7) and tributyl (vinyl) tin orallyltributyltin are made to react in the presence of a palladiumcatalyst in the absence of a solvent or in an inert solvent to produceCompound (8).

The usable solvent is not particularly limited as long as it candissolve the starting materials to some extent and does not inhibit thereaction, and includes, for example, aromatic hydrocarbons such asbenzene, toluene, xylene; ethers such as dioxane, dimethoxyethane,tetrahydrofuran; amides such as N,N-dimethylformamide, and it ispreferably tetrahydrofuran or N,N-dimethylformamide.

The usable palladium catalyst includes, for example, a palladiumcatalyst such as dichlorobis(triphenylphosphine)palladium(II),tetrakis(triphenylphosphine)palladium(0),tris(dibenzylideneacetone)dipalladium(0),bis(dibenzylideneacetone)palladium(0),bis(tri-t-butylphosphine)palladium(0), palladium black, etc., andpreferably dichlorobis(triphenylphosphine)palladium(II) ortetrakis(triphenylphosphine)palladium(0).

Although the reaction temperature may vary depending on startingmaterials, solvent, palladium catalysts, etc., it is typically 50 to200° C., and preferably 70 to 150° C.

Although the reaction time may vary depending on starting materials,solvent, palladium catalyst, reaction temperature, etc., it is typically30 minutes to 48 hours, and is preferably 5 to 12 hours.

(Step B-5) Reduction Reaction

This step is a step where hydrogen is made to react with Compound (8) inthe absence of a solvent or in an inert solvent, in the presence of areduction catalyst, or a reducing agent is made to react with Compound(8) in the absence of a solvent or in an inert solvent, and a nitrogroup and an alkenyl group is converted into an amino group and an alkylgroup.

Also included in this step is a step where when R¹ is a C2-C6 alkynylgroup, only a nitro group is reduced without reducing the triple bond.

The usable solvent is not particularly limited as long as it candissolve the starting materials to some extent and does not inhibit thereaction, and includes, for example, alcohols such as methanol, ethanol,n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamylalcohol, diethylene glycol, glycerin, octanol, cyclohexanol, methylcellosolve; ethers such as diethyl ether, diisopropyl ether,tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethylether; aliphatic hydrocarbons such as hexane, heptane, ligroin,petroleum ether; organic acid esters such as ethyl acetate, andpreferably ethers, aliphatic hydrocarbons, alcohols, organic acid ester,or a mixture of these, and most preferably methanol or tetrahydrofuran.

The usable catalyst includes, for example, palladium-carbon, Raneynickel, nickel (II) chloride, platinum oxide, platinum black,rhodium-aluminum oxide, triphenylphosphine-rhodium chloride,palladium-barium sulfate, etc., and preferably palladium/carbon ornickel (II) chloride. When progress of the reaction is slow, a reductioncatalyst can also be used in an amount of the weight ratio to thematerials of about 1/2.

Although the reaction temperature in the case of using a reductioncatalyst may vary depending on starting materials and solvents, it istypically 0 to 60° C., and preferably 10 to 40° C.

Although the reaction time in the case of using a reduction catalyst mayvary depending on starting materials, solvent, and reaction temperature,it is typically 1 to 60 hours and preferably 5 to 24 hours.

Typically, the hydrogen pressure at the time of the reaction in the caseof using a reduction catalyst is 0.5 to 5 atm, and preferably 1 to 2atm.

In the case where an alkenyl group is reduced simultaneously with anitro group, nickel (II) chloride is used as a catalyst and the reactioncan be performed with sodium borohydride, etc., at −30 to 40° C.(preferably −15 to 25° C.) for 30 minutes to 1 hour.

In addition, when R¹ is a C2-C6 alkynyl group, and in the case that onlythe nitro group is reduced without reducing the triple bond, thereaction can be performed using iron-hydrochloric acid, zinc-aceticacid, iron-ammonium chloride, etc., at 0 to 30° C. for 10 to 50 hours.

Typically, the compound obtained at the B-5 step can be used in thefollowing B-6 step by merely filtering the catalyst off.

(Step B-6) Cyclization Reaction

This step is a step where carbon bisulfide is made to react with thecompound obtained at the above described B-5 step in the absence of asolvent or in an inert solvent to produce Compound (2) which is anintermediate in the above described Process A.

The usable solvent is not particularly limited as long as it candissolve the starting materials to some extent and does not inhibit thereaction, and includes, for example alcohols such as methanol, ethanol,n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamylalcohol, diethylene glycol, glycerin, octanol, cyclohexanol, methylcellosolve; aliphatic hydrocarbons such as hexane, heptane, ligroin,petroleum ether; aromatic hydrocarbons such as benzene, toluene, etherssuch as dioxane, dimethoxyethane, diethylene glycol dimethyl ether;halogenated hydrocarbons such as chloroform, dichloromethane,1,2-dichloroethane, carbon tetrachloride; amides such as formamide,N,N-dimethylformamide, N,N-dimethylacetamide, hexamethylphosphorictriamide; organic acid such as acetic acid, etc., preferably an alcoholand most preferably methanol or N,N-dimethylformamide.

Although the reaction temperature may vary depending on startingmaterials and solvent, it is typically 0 to 60° C., and preferably 10 to40° C.

Although the reaction time may vary depending on starting materials,solvent, and reaction temperature, it is typically 12 to 60 hours andpreferably 24 to 48 hours.

(Step B-7)

This step is a step where ammonia is made to react with Compound (4a) inthe presence or absence of alkaline metal carbonate in the absence of asolvent or in an inert solvent to produce Compound (6). This step can beperformed according to the B-1 step.

As Compound (4a), a commercially available compound or a compoundsynthesized based on a process known by publication can be used.

Compound (2a) in which R² of Compound (2) is methyl group can beproduced by the following Process C.

In the above scheme, R¹ is as defined above, X⁴ represents a leavinggroup, preferably a fluorine atom, a chlorine atom, a bromine atom, oran iodine atom, and more preferably a fluoride atom.

(Step C-1) R¹—O Group Introducing Reaction

This step is a step where Compound (9), and an alcohol or phenol R¹—OH(wherein R¹ is as defined above) is made to react with produce Compound(10).

As Compound (9), a commercially available compound or a compoundsynthesized based on a process known by publication can be used.

This process can be performed according to the above described B-2 step.

(Step C-2) Nitration Reaction

This step is a step where fuming nitric acid is made to react withCompound (10) in the presence or absence of concentrated sulfuric acid,in the absence of a solvent to produce Compound (11).

Although the reaction temperature may vary depending on startingmaterials and solvent, it is typically −20 to 100° C., and morepreferably 0 to 80° C.

Although the reaction time may vary depending on starting materials,solvent, and reaction temperature, it is typically 6 to 48 hours andpreferably 7 to 36 hours.

(Step C-3) Reduction Reaction

This step is a step where hydrogen is made to react with Compound (11)in the presence of a reduction catalyst in the absence of a solvent orin an inert solvent to produce Compound (12). This process can beperformed according to the above described step B-5.

(Step C-4) Nitro Group Introduction Reaction

This step is a step where Compound (12) is made to react in an anhydrousacetic acid at 0 to 40° C. for 1 to 10 hours to obtain a compoundconverted into N-acetyl form (Step C-4-1), subsequently fuming nitricacid is made to react with Compound (12) in the presence or the absenceof concentrated sulfuric acid, in the absence of a solvent at 0 to 40°C. for 1 to 10 hours to obtain Compound (13) (Step C-4-2), and further,the compound obtained at the preceeding step is made to react with analkaline metal hydroxide such as sodium hydroxide in an alcohol such asmethanol and ethanol or a mixture of the alcohol and water at 0 to 40°C. for 5 to 30 minutes to produce Compound (13).

(Step C-5) Reduction Reaction

This step is a step where hydrogen gas is made to react with Compound(13) in the presence of a reduction catalyst in the absence of a solventor in an inert solvent, to convert a nitro group into an amino group.This process can be performed according to the above described step B-5.

(Step C-6) Cyclization Reaction

This step is a step where carbon bisulfide is made to react with thecompound obtained at the above described step C-5 in the absence of asolvent or in an inert solvent to produce Compound (2a) in which R² ismethyl group among the intermediates of the above described Process A.This process can be performed according to the above described step B-6.

Compound (3a) in which R³ of Compound (3) is ethyl group can be producedby the following Process D.

In the above scheme, R⁴, R⁵ and X¹ represent the same as defined above,Y¹ represents a trialkylsilyl group, preferably trimethylsilyl group andX⁶ represents an alkylsulfonyl group which may be substituted with ahalogen atom or a benzene sulfonyl group which may be substituted (forexample, with trifluoromethanesulfonyl, methanesulfonyl, ethanesulfonyl,benzenesulfonyl, p-toluenesulfonyl group, etc.).

(Step D-1) Leaving Group Introduction Reaction

This step is a step where Compound (14) and a leaving group introductionagent are made to react in the presence of a base in the absence of asolvent or in an inert solvent to produce Compound (15).

As Compound (14), a commercially available compound or a compoundsynthesized based on a process known by publication can be used.

The usable solvent is not particularly limited as long as it candissolve the starting materials to some extent and does not inhibit thereaction, and includes, for example, halogenated hydrocarbons such aschloroform, dichloromethane, 1,2-dichloroethane, carbon tetrachloride;aromatic, hydrocarbon such as benzene, toluene; ethers such as diethylether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane,diethylene glycol dimethyl ether; amides such as formamide,N,N-dimethylformamide, N,N-dimethylacetamide, hexamethylphosphorictriamide, pyridine, etc., and preferably a halogenated hydrocarbon andmost preferably dichloromethane.

The usable leaving group introduction agent includes, for example,sulfonyl halides such as methanesulfonylchloride,p-toluenesulfonylchloride, trifluoromethanesulfonylchloride,N-phenyl-bis(trifluoromethanesulfonimide), and preferablyN-phenyl-bis(trifluoromethanesulfonimide).

The usable base includes, for example, tertiary alkylamines such astrimethylamine and triethylamine, pyridines, etc., and it is preferablytriethylamine.

Although the reaction temperature may vary depending on startingmaterials, solvent, leaving group introduction agent and bases, it istypically 0 to 100° C., and preferably 0 to 40° C.

Although the reaction time may vary depending on starting materials,solvent, leaving group introduction agent, base, and reactiontemperature, it is typically 6 to 48 hours and preferably 12 to 30hours.

(Step D-2) Alkyne Introduction Reaction

This step is a step where Compound (15) and (trialkylsilyl)acetylene aremade to react in the presence of a palladium catalyst, a copper catalystand a base in the absence of a solvent or in an inert solvent, and undernitrogen atmosphere to produce Compound (16).

The usable solvent is not particularly limited as long as it candissolve the starting materials to some extent and does not inhibit thereaction, and includes, for example, ethers such as diethyl ether,tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethylether; amides such as formamide, N,N-dimethylformamide,N,N-dimethylacetamide, hexamethylphosphoric triamide, pyridine, etc.,and preferably an amide and most preferably N,N-dimethylformamide.

The usable palladium catalyst includes, for example,dichlorobis(triphenylphosphine)palladium(0),tetrakis(triphenylphosphine)palladium(0),tris(dibenzylideneacetone)dipalladium(0),bis(dibenzylideneacetone)palladium(0),bis(tri-t-butylphosphine)palladium(0), palladium black, etc., andpreferably dichlorobis(triphenylphosphine)palladium(0).

The usable copper catalyst includes, for example, copper (powder),copper(I) chloride, copper(II) chloride, copper(I) iodide, copper(I)oxide, copper(II) oxide, copper(II) acetate, copper(II) sulfatepentahydrate, copper(II) acetylacetonate, copper(I) thiocyanate, etc.,and preferably copper(I) iodide.

The usable base includes, for example, N-methylmorpholine,triethylamine, tripropylamine, tributylamine, diisopropylethylamine,dicyclohexylamine, N-methylpiperidine, pyridine, 4-pyrrolidinopyridine,picoline, 4-(N,N-dimethylamino)pyridine,2,6-di(t-butyl)-4-methylpyridine, quinoline, N,N-dimethyl aniline,N,N-diethyl aniline, 1,5-diazabicyclo[4.3.0]nona-5-ene (DBN),1,4-diazabicyclo[2.2.2]octane (DABCO),1,8-diazabicyclo[5.4.0]undeca-7-ene (DBU) etc., and it is preferablytriethylamine.

The usable (trialkylsilyl)acetylene includes, for example,(trimethylsilyl)acetylene, (triethylsilyl)acetylene, etc., and it ispreferably (trimethylsilyl)acetylene.

Although the reaction temperature may vary depending on startingmaterials, solvent, a palladium catalyst, copper catalyst, base and(trialkylsilyl)acetylene, it is typically 10 to 100° C., and preferably30 to 80° C.

Although the reaction time may vary depending on starting materials,solvent, palladium catalyst, copper catalyst, base,(trialkylsilyl)acetylene and reaction temperature, it is typically 10minutes to 4 hours, and preferably 30 minutes to 3 hours.

(Step D-3) Desilylation Reaction, Reduction Reaction

This process consists of the following 2 reaction steps.

(1) Desilylation Reaction

This step is a step where a desilylating agent was made to react toCompound (16) in the absence of a solvent or in an inert solvent toproduce a desilylated compound.

The usable solvent is not particularly limited as long as it candissolve the starting materials to some extent and does not inhibit thereaction, and includes, for example, alcohols such as methanol, ethanol,n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamylalcohol, diethylene glycol, glycerin, octanol, cyclohexanol and methylcellosolve; aliphatic hydrocarbons such as hexane, heptane, ligroin,petroleum ether; halogenated hydrocarbons such as chloroform,dichloromethane, 1,2-dichloroethane and carbon tetrachloride; etherssuch as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane,dimethoxyethane, diethylene glycol dimethyl ether; amides such asformamide, N,N-dimethylformamide, N,N-dimethylacetamide,hexamethylphosphoric triamide, and it is preferably an ether and mostpreferably tetrahydrofuran.

The usable desilylating agent includes, for example, hydrogen fluoride,tetrabutylammonium fluoride, etc., and it is preferablytetrabutylammonium fluoride.

Although the reaction temperature may vary depending on startingmaterials, solvent, and desilylating agent, it is typically 0 to 100°C., and preferably 10 to 40° C.

Although the reaction time may vary depending on starting materials,solvent, and desilylating agent, it is typically 30 minutes to 6 hours,and preferably 2 to 3 hours.

Since the compound obtained in this step may be a low boiling pointcompound, and in that case, the solution is typically used for thesubsequent process without any treatment of concentration afterreaction, extraction, column chromatography, etc.

(2) Reduction Reaction

This step is a step where hydrogen gas is made to react with thecompound obtained at the above described step (1) in the presence of areduction catalyst in an inert solvent to produce Compound (17).

This process can be performed according to the above described step B-2.However, the reduction catalyst is typically used in a weight ratio ofabout 5-10% to the compound obtained at the above described step (1).

(Step D-4) Oxidation Reaction

This step is a step where an oxidizing reagent is made to react withCompound (17) in the absence of a solvent or in an inert solvent toproduce Compound (18).

The usable solvent is not particularly limited as long as it candissolve the starting materials to some extent and does not inhibit thereaction, and includes, for example, aliphatic hydrocarbons such ashexane, heptane, ligroin, petroleum ether; halogenated hydrocarbons suchas chloroform, dichloromethane, 1,2-dichloroethane, carbontetrachloride; ethers such as diethyl ether, diisopropyl ether,tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethylether; amides such as formamide, N,N-dimethylformamide,N,N-dimethylacetamide, hexamethylphosphoric triamide; organic acids suchas acetic acid, etc., and it is preferably an organic acid and mostpreferably acetic acid.

The usable oxidizing reagent includes, for example, hydrogen peroxide,t-butyl hydroperoxide, sodium periodate, peracetic acid, perbenzoicacid, metachloroperbenzoic acid, urea-hydrogen peroxide additioncompound, etc., and it is preferably hydrogen peroxide or urea-hydrogenperoxide addition compound. In addition, when using urea-hydrogenperoxide addition compound, it is usually desirable to use the compoundalong with anhydrous trifluoroacetic acid and the like.

Although the reaction temperature may vary depending on startingmaterials, solvent, and oxidizing reagent, it is typically 30 to 150°C., and preferably 50 to 100° C.

Although the reaction time may vary depending on starting materials,solvent, oxidizing reagent and reaction temperature, it is typically 12to 60 hours and preferably 24 to 36 hours.

(Step D-5) Nitration Reaction

This step is a step where fuming nitric acid is made to react withCompound (18) in the absence or presence of concentrated sulfuric acidin the absence of a solvent or in an inert solvent to produce Compound(19).

This step can be performed according to the above described step C-2.

(Step D-6) R⁴—O Forming Reaction

This step is a step where an alcoholic R⁴—OH (wherein R⁴ is as definedabove) is made to react with Compound (19) in the presence of a base inthe absence of a solvent or in an inert solvent to produce Compound(20).

The usable solvent is not particularly limited as long as it candissolve the starting materials to some extent and does not inhibit thereaction, and includes, for example, alcohols such as methanol, ethanol,n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamylalcohol, diethylene glycol, glycerin, octanol, cyclohexanol and methylcellosolve; aliphatic hydrocarbons such as hexane, heptane, ligroin,petroleum ether; halogenated hydrocarbons such as chloroform,dichloromethane, 1,2-dichloroethane and carbon tetrachloride; etherssuch as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane,dimethoxyethane, diethylene glycol dimethyl ether; amides such asformamide, N,N-dimethylformamide, N,N-dimethylacetamide andhexamethylphosphoric triamide; organic acid such as acetic acid, etc.,and it is preferably an alcohol (R⁴—OH).

The usable base includes, for example, alkaline metal alkoxide such assodium methoxide and sodium ethoxide, and it is preferably sodiumalkoxide (desired R⁴—ONa).

Although the reaction temperature may vary depending on startingmaterials, solvent and base, it is typically 0 to 100° C., andpreferably 10 to 60° C.

Although the reaction time may vary depending on the starting materials,solvent, base and reaction temperature, it is typically 5 to 24 hoursand preferably 8 to 14 hours.

(Step D-7) Acetic Acid Esterification Reaction

This step is a step where anhydrous acetic acid is made to react withCompound (20) in the absence of a solvent to produce an acetic acidester of Compound (21).

Although the reaction temperature may vary depending on startingmaterials and solvent, it is typically 20 to 150° C., and preferably 50to 100° C.

Although the reaction time may vary depending on starting materials,solvent and reaction temperature, it is typically 10 minutes to 3 hours,and preferably 1 to 2 hours.

The residue after the reaction obtained by evaporating anhydrous aceticacid is typically used for the subsequent step without any treatment.

(Step D-8) Hydrolysis Reaction

This step is a step where a base is made to react with the compoundobtained at the above described step D-7 process in the absence of asolvent or in an inert solvent to produce Compound (21).

The usable solvent is not particularly limited as long as it candissolve the starting materials to some extent and does not inhibit thereaction, and includes, for example, water; alcohols such as methanol,ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol,isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol andmethyl cellosolve; aliphatic hydrocarbons such as hexane, heptane,ligroin, petroleum ether; ethers such as dioxane, dimethoxyethane,diethylene glycol dimethyl ether; halogenated hydrocarbons such aschloroform, dichloromethane, 1,2-dichloroethane and carbontetrachloride; ethers such as diethyl ether, diisopropyl ether,tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethylether; amides such as formamide, N,N-dimethylformamide,N,N-dimethylacetamide, hexamethylphosphoric triamide, and it ispreferably an alcohol or a mixture of alcohol and water, and mostpreferably a mixture of methanol and water.

The usable base includes, for example, alkaline metal carbonates such aslithium carbonate, sodium carbonate, potassium carbonate; alkaline metalhydroxide such as lithium hydroxide, sodium hydroxide, potassiumhydroxide; metal alkoxide such as lithium methoxide, sodium methoxide,sodium ethoxide, potassium t-butoxide; ammonia such as aqueous ammoniasolution, concentrated ammonia-methanol, etc., and it is preferably analkaline metal hydroxide and most preferably sodium hydroxide.

Although the reaction temperature may vary depending on startingmaterials, solvent and base, it is typically 0 to 60° C., and preferably10 to 40° C.

Although the reaction time may vary depending on the starting materials,solvent, base and reaction temperature, it is typically 10 minutes to 2hours, and preferably 30 minutes to 1 hour.

(Step D-9)

(1) Halogenation Reaction (Illustrated by Chlorination Reaction as aRepresentative Reaction)

This step is a step where a chlorinating agent is made to react withCompound (21) in the absence of a solvent or in an inert solvent toproduce Compound (3a) in which R³ is an ethyl group among theintermediates of the above described Process A.

The usable solvent is not particularly limited as long as it candissolve the starting materials to some extent and does not inhibit thereaction, and includes, for example, halogenated hydrocarbons such aschloroform, dichloromethane, 1,2-dichloroethane, carbon tetrachloride,and it is preferably a halogenated hydrocarbon and most preferablydichloromethane.

The usable chlorinating agent includes, for example, chlorine, oxalylchloride, thionyl chloride, phosphorus oxychloride, phosphorustrichloride, phosphorus pentachloride, etc., and it is preferablythionyl chloride.

Although the reaction temperature may vary depending on startingmaterials, solvent and chlorinating agents, it is typically −20 to 30°C., and preferably 0 to 10° C.

Although the reaction time may vary depending on starting materials,solvent, chlorinating agent and reaction temperature, it is typically 30minutes to 6 hours, and preferably 1 to 2 hours.

Compound (3a) of this step can be obtained as a hydrochloride salt, andcan also be used without any treatment.

(2) Leaving Group Introduction Reaction

This step is a step where Compound (21) and a leaving group introductionagent are made to react in the presence of base in the absence of asolvent or in an inert solvent to produce Compound (3a) in which R² ismethyl group. This step can be performed such as the above describedstep D-1.

Compound (2b) in which R² of Compound (2) is methyl group can be alsoproduced by the following Process E.

In the above scheme, R^(1b) is as defined above, and X⁵ represents aleaving group and is a chlorine atom, a bromine atom or an iodine atom,and preferably a chlorine atom.

(Step E-1) Oxidation Reaction

This step is a step where an oxidizing reagent is made to react withCompound (22) or Compound (22a) in the absence of a solvent or in aninert solvent to produce Compound (23) or Compound (23a).

As Compounds (22) and (22a), commercially available compounds orcompounds synthesized according to any process known by publication canbe used.

This step can be performed according to the above described step D-4.

(Step E-2) Leaving Group Introduction Reaction (Illustrated byChlorination Reaction as a Representative Reaction)

This step is a step where a chlorinating agent is made to react withCompound (23) or Compound (23a) in the presence of a base in the absenceof a solvent or in an inert solvent to produce Compound (24).

The usable solvent is not particularly limited as long as it candissolve the starting materials to some extent and does not inhibit thereaction, and includes, for example, halogenated hydrocarbons such aschloroform, dichloromethane, 1,2-dichloroethane, carbon tetrachloride,and it is preferably a halogenated hydrocarbon and most preferablydichloromethane.

The usable base includes, for example, N-methylmorpholine,triethylamine, tripropylamine, tributylamine, diisopropylethylamine,dicyclohexylamine, N-methylpiperidine, pyridine, 4-pyrrolidinopyridine,picoline, 4-(N,N-dimethylamino)pyridine,2,6-di(t-butyl)-4-methylpyridine, quinoline, N,N-dimethyl aniline,N,N-diethyl aniline, 1,5-diazabicyclo[4.3.0]nona-5-ene (DBN),1,4-diazabicyclo[2.2.2]octane (DABCO),1,8-diazabicyclo[5.4.0]undeca-7-ene (DBU), etc., and it is preferablytriethylamine.

The usable chlorinating agent includes, for example, chlorine, oxalylchloride, thionyl chloride, phosphorus oxychloride, phosphorustrichloride, phosphorus pentachloride, etc., and it is preferablythionyl chloride.

Although the reaction temperature may vary depending on startingmaterials, solvent and chlorinating agents, it is typically −20 to 30°C., and preferably 0 to 10° C.

Although the reaction time may vary depending on starting materials,solvent, chlorinating agent and reaction temperature, it is typically 30minutes to 6 hours, and preferably 1 to 2 hours.

(Step E-3) Nitration Reaction

This step is a step where fuming nitric acid is made to react withCompound (24) in the absence or presence of concentrated sulfuric acidin the absence of a solvent to produce Compound (25).

This process can be performed according to the above described step C-2.

(Step E-4) Amination Reaction

This step is a step where aqueous ammonia solution is made to react withCompound (25) in the presence of alkaline metal carbonate in the absenceof a solvent or in an inert solvent to produce Compound (26). This stepcan be performed according to the above described step B-1.

(Step E-5) R¹—O-Group Introduction Reaction

This step is a step where Compound (26) and an alcohol or phenol R¹—OH(wherein R¹ is as defined above) is made to react, to produce Compound(27).

This step can be performed according to the above described step B-2.

(Step E-6) Reduction Reaction

This step is a step where hydrogen is made to react with Compound (27)in the presence of a reduction catalyst in the absence of a solvent orin an inert solvent, and a nitro group is converted to an amino group.This step can be performed according to the above described step B-5.

(Step E-7) Cyclization Reaction

This step is a step where carbon bisulfide is made to react with thecompound obtained at the above described step B-5 in the absence of asolvent or in an inert solvent to produce Compound (2b) in which R² ismethyl group among the intermediates of the above described Process A.This step can be performed according to the above described step B-6.

The object compound of each step can be extracted from the reactionmixture according to ordinary process after each step of each of theabove processes is ended.

For example, when the whole reaction mixture is a liquid, the reactionmixture is optionally allowed to be cooled to room temperature orice-cooled, and the acid, alkali, oxidizing reagent, or reducing agentis suitably neutralized, and an organic solvent which is immiscible likewater and ethyl acetate and does not react with the object compound isadded, and the layer containing the object compound is separated. Next,a solvent which does not mix with the obtained layer and does not reactwith the object compound is added, the layer containing the objectcompound is washed, and the layer concerned is separated. In addition,if the layer concerned is an organic layer, it can be dried using adrying agent such as anhydrous magnesium sulfate or anhydrous sodiumsulfate, and the object compound can be taken out by evaporating thesolvent. If the layer concerned is an aqueous layer, after it iselectrically desalted, the object compound can be obtained byfreeze-drying.

In addition, in the case that the whole reaction mixture is a liquid,and if possible, the object compound can be taken out only byevaporating substances other than the object compound (for example,solvent, reagents, etc.) under ordinary or reduced pressure.

Furthermore, when only the object compound has precipitated as a solid,or when the above described whole reaction mixture is a liquid and onlythe object compound has precipitated as a solid in process of obtainingthe compound, first, the object compound is taken out by filteringmethod and the obtained object compound is washed with a suitableorganic or inorganic solvent, and then dried, and the mother liquid istreated just like the above described case where the whole reactionmixture is a liquid to further obtain the object compound.

Furthermore, when only a reagent or catalyst exists as a solid, or whenthe above described whole reaction mixture is a liquid and only areagent or catalyst precipitates as a solid in process of extraction andthe object compound is dissolving in the solution, the reagent orcatalyst is first filtered off by the filtering method, and the objectcompound is washed with a suitable organic or inorganic solvent, and theresulting washing liquid is combined with the mother liquid, and theresulting mixed solution is treated just like the above described casewhere the whole reaction mixture is a liquid to obtain the objectcompound.

Especially when those contained in the reaction mixture other than theobject compound do not inhibit the reaction of the subsequent step, thereaction mixture can also be used without any treatment for thesubsequent step without particularly isolating the object compound.

For the purpose of improving the purity of the object compound extractedby the above described method, recrystallization method, variouschromatography methods, and distillation method can be suitablyperformed.

When the extracted object compound is a solid, the purity of the objectcompound can typically be improved by recrystallization method. In therecrystallization method, a single solvent or two or more mixtures whichdo not react with the object compound can be used. Specifically, theobject compound is first dissolved in a single or multiple solventswhich do not react with the object compound at room temperature or underheating. The resulting mixed solution is cooled with iced water orallowed to leave at room temperature, and the object compound is allowedto recrystallize from the mixed solution.

When the extracted object compound is a liquid, the purity of the objectcompound can be improved by various chromatography methods. Generally,weak acidic silica-gels such as Silica Gel 60 produced by Merck Co.(70-230 mesh or 340-400 mesh) or BW-300 produced by Fuji SilysiaChemical Co., Ltd. (300 mesh) can be used. When the object compound hasbasic properties, and the above described silica gels are excessivelyadsorptive, propylamine coating silica gel (200-350 mesh) by FujiSilysia Chemical Co., Ltd. etc., can also be used. When the objectcompound has bipolarity, or when it is required to be eluted with a highpolarity solvent such as methanol, NAM-200H or NAM-300H produced by NAMUResearch Institute can also be used. The object compound whose purity isimproved can be obtained by using these silica gels and eluting theobject compound with a single or multiple solvents which do not reactwith the object compound, and evaporating the solvent.

When the extracted object compound is a liquid, the purity of the objectcompound can be improved also by distillation method. The objectcompound can be distilled under reduced pressure at room temperature orunder heating in the distillation method.

The above is to illustrate representative examples of the process forproducing Compound (1) of the present invention, and the materialcompounds and the various reagents in the production of the presentinvention may form a salt, hydrate or solvate, and each of them may varydepending on starting materials, solvents to be used, etc., and are notparticularly limited unless they do not inhibit the reaction. The usablesolvents may vary depending on starting materials, reagents, etc., andneedless to say, they are not particularly limited as long as they candissolve the starting materials to some extent and do not inhibit thereaction. When Compound (1) concerning the present invention is obtainedas a free form, it can be converted to the state of a salt or hydratethereof which the above described Compound (1) may form according to anordinary process.

When Compound (1) of the present invention is obtained as a salt orhydrate of Compound (1), it can converted to a free form of the abovedescribed Compound (1) according to an ordinary process.

Moreover, various isomers (for example, geometric isomer, opticalisomer, rotational isomer, stereoisomer, tautomer, etc.) obtainable forCompound (1) of the present invention can be purified and isolated byusing usual separation means, for example, recrystallization,diastereomer salt method, enzymatic dividing method, and variouschromatography (for example, thin layer chromatography, columnchromatography, gas chromatography, etc.).

When the compound of the present invention is used as drug, typically,suitable additive agents are mixed with the compound of the presentinvention to form preparation. However, this does not deny the use ofthe compound of the present invention without any treatment as a drug.

As the above described additive agent generally used for drugs,excipient, binder, lubricant, disintegrating agent, colorant, flavor,emulsifier, surfactant, dissolution auxiliary agent, suspending agent,isotonizing agent, buffering agent, antiseptic, anti-oxidizing agent,stabilizing agent, absorption improver, etc. can be mentioned, and thesecan also be optionally used in a suitable combination.

Examples of the above described excipient include lactose, sucrose,glucose, cornstarch, mannitol, sorbitol, starch, gelatinized starch,dextrin, crystalline cellulose, light anhydrous silicic acid, aluminumsilicate, calcium silicate, magnesium aluminometasilicate, calciumhydrogen phosphate, etc.

Examples of the above described binder include polyvinyl alcohol, methylcellulose, ethyl cellulose, gum arabic, gum tragacanth, gelatin,shellac, hydroxypropyl methylcellulose, hydroxypropyl cellulose,carboxymethylcellulose sodium, polyvinylpyrrolidone, macrogol, etc.

Examples of the above described lubricant include magnesium stearate,calcium stearate, sodium stearyl fumarate, talc, polyethylene glycol,colloidal silica, etc.

Examples of the above described disintegrating agent include crystalcellulose, agar, gelatin, calcium carbonate, sodium bicarbonate, calciumcitrate, dextrin, pectin, low substituted hydroxypropylcellulose,carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellosesodium, carboxymethyl starch, carboxymethyl starch sodium, etc.

Examples of the above described colorant include those permitted to addto drugs such as iron sesquioxide, yellow iron sesquioxide, carmine,caramel, beta-carotene, titanium oxide, talc, riboflavin sodiumphosphate, and yellow aluminum lake.

Examples of the above described flavor include cocoa powder, peppermint,aromatic powder, peppermint oil, camphol, cinnamon powder, etc.

Examples of the above described emulsifier or surfactant includestearyltriethanolamine, sodium lauryl sulfate, lauryl aminopropionate,lecithin, glyceryl monostearate, sucrose fatty acid ester, glycerinfatty acid ester, etc.

Examples of the above described dissolution auxiliary agent includepolyethylene glycol, propylene glycol, benzoic acid benzyl ester,ethanol, cholesterol, triethanolamine, sodium carbonate, sodium citrate,Polysorbate 80, nicotinamide, etc.

Examples of the above described suspending agent include, besides theabove described surfactant, hydrophilic polymers such as polyvinylalcohol, polyvinylpyrrolidone, methyl cellulose, hydroxymethylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose.

Examples of the above described isotonizing agent include glucose,sodium chloride, mannitol, sorbitol, etc.

Examples of the above described buffering agent include buffer solutionsuch as phosphate, acetate, carbonate, citrate, etc.

Examples of the above described antiseptic include methylparaben, propylparaben, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroaceticacid, sorbic acid, etc.

Examples of the above described anti-oxidizing agent include sulfurousacid salt, ascorbic acid, alpha-tocopherol, etc.

Examples of the above described stabilizing agent include thosegenerally used for drugs.

Examples of the above described absorption improver include thosegenerally used for drugs.

Examples of the above described preparation include oral agent such astablet, powder drug, granule agent, capsule agent, syrup agent, trocheagent, and inhalation agent; external preparations such as suppository,ointment, eye ointment, tapes, eye drop, nose drop, ear drop, pap agent,lotion or an injection agent.

The above described oral agent is prepared by suitably combining theabove described additives. The surface of it may be coated if needed.

The above described external preparations is prepared by suitablycombining the above described additives, particularly excipient, binder,flavor, emulsifier, surfactant, dissolution auxiliary agent, suspendingagent, isotonizing agent, antiseptic, anti-oxidizing agent, stabilizingagent or absorption improver.

The above described injection agent prepared by suitably combining theabove described additives, particularly emulsifier, surfactant,dissolution auxiliary agent, suspending agent, isotonizing agent,buffering agent, antiseptic, anti-oxidizing agent, stabilization agentor absorption improver.

When using the compound of the present invention as drug, the dosagevaries depending on condition or age, and typically, 0.15 to 5000 mg(preferably 0.5 to 1500 mg) in the case of oral agent, 0.5 to 1500 mg(preferably 1.5 to 500 mg) in the case of external preparation, 0.3 to5000 mg (preferably 1 to 500 mg) for one time or divided to 2 to 6 timesper day in the case of injection agent. The above described values areactually administered values for oral agent and injection agent and avalue actually absorbed by a living body for external preparation.

Compound (1) of the present invention can be produced, for example, bythe process indicated in the following Examples, and the effect of thecompound can be confirmed by the method indicated for the following TestExamples. However, they are illustrative and present invention are notlimited to these specific examples below in any case.

Commercially available starting materials, reagents, used in Examplesand their suppliers are shown below. When the supplier is indicated by apublication name, it means that the compound was prepared according tothe reference shown.

-   2-Fluoro-3-methylpyridine (FLUOROCHEM)-   10% Pd-on-carbon powder (50% water content article) (N. E. CHEMCAT)-   Carbon bisulfide (Wako Pure Chemical Industries)-   2-Chloromethyl-4-methoxy-3-methylpyridine hydrochloride salt (J.    Med. Chem., 1992, 35, 1049-1057)-   Metachloro perbenzoic acid (Tokyo Kasei Kogyo)-   1N sodium hydroxide solution (Wako Pure Chemical Industries)-   2-Chloro-3-methylpyridine (Aldrich)-   Urea hydrogen peroxide addition compound (Aldrich)-   Anhydrous trifluoroacetic acid (Tokyo Kasei Kogyo)-   2-Chloro-5-methylpyridine (Aldrich)-   Phosphorous oxychloride (Wako Pure Chemical Industries)-   Anhydrous trifluoromethane sulfonic acid (Tokyo Kasei Kogyo)-   Nitric acid tetramethyl ammonium (Aldrich)-   2,2,2-trifluoro ethanol (Tokyo Kasei Kogyo)-   2,2-difluoro ethanol (Lancaster)-   2-Chloro-6-methoxy-3-nitropyridine (Tokyo Kasei Kogyo)-   Concentrated ammonia solution (Kanto chemistry)-   N-iodosuccinimide (Lancaster)-   Acetic acid (Wako Pure Chemical Industries)-   Trimethylboroxin (Aldrich)-   Tetrakis-(triphenylphosphine)palladium(0) (Kanto chemistry)

EXAMPLES Example 15-Methoxy-2-(((4-methoxy-3-methyl-2-pyridinyl)methyl)sulfinyl)-6-methyl-3H-imidazo[4,5-b]pyridineSodium salt

(1a) 2-Methoxy-3-methylpyridine

A mixture of 2-fluoro-3-methylpyridine (2.34 g, 21.1 mmol) and a 28%sodium methoxide methanol solution (7.72 g, 40 mmol) was stirred for 15minutes under reflux. After the reaction was completed, water was pouredinto the reaction mixture, and after neutralized, the reaction mixturewas extracted with ethyl acetate, dried over magnesium sulfate, and thesolvent was evaporated, thereby yielding the title compound (1.62 g,13.1 mmol, 62%) as a colorless liquid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm;2.13 (3H, s), 3.86 (3H, s), 6.87-6.90 (1H, m), 7.49-7.55 (1H, m),7.96-8.02 (1H, m).(1b) 2-Methoxy-3-methyl-5-nitropyridine

Concentrated sulfuric acid (5 ml) and fuming nitric acid (5 ml) wereadded to 2-methoxy-3-methylpyridine (1.61 g, 13.1 mmol) under icecooling, and stirred at 0° C. for 1 hour and further stirred at roomtemperature overnight. The reaction mixture was poured onto ice,neutralized with ammonia solution, extracted with ethyl acetate, driedover magnesium sulfate, the solvent was evaporated, thereby yielding thetitle compound (1.63 g, 9.71 mmol, and 74%). ¹H NMR (400 MHz, DMSO-d₆) δppm; 2.25 (3H, s), 4.04 (3H, s), 8.37-8.40 (1H, m), 8.92-8.95 (1H, m).(1c) 6-Methoxy-5-methyl-3-pyridinamine

2-Methoxy-3-methyl-5-nitropyridine (1.63 g, 9.71 mmol) was dissolved inmethanol (50 ml), 10% Pd-on-carbon powder (50% water content article)(800 mg) was added, and stirred under hydrogen atmosphere for 2 hoursand 10 minutes. After the reaction was completed, celite filtration wascarried out, the solvent was evaporated, thereby yielding the titlecompound (1.25 g, 0.90 mmol, 93%) as a blue oily substance. ¹H NMR (400MHz, DMSO-d₆) δ ppm; 2.03 (3H, s), 3.73 (3H, s), 4.62 (2H, br s),6.83-6.86 (1H, m), 7.31-7.34 (1H, m).(1d) N-(6-methoxy-5-methyl-2-nitro-3-pyridinyl)acetamide

Anhydrous acetic acid (20 ml) was added to6-methoxy-5-methyl-3-pyridineamine (1.18 g, 8.54 mmol) under icecooling, and stirred at 0° C. for 20 minutes and at room temperaturefurther for 1 hour. The reaction mixture was cooled at 0° C. again,fuming nitric acid (2 ml) was dropped thereto, and the mixture wasstirred at 0° C. for 1 hour and 55 minutes and at room temperaturefurther for 1 hour and 45 minutes. The reaction mixture was poured ontoice and adjusted to pH 9 with a 5N sodium hydroxide solution, extractedwith ethyl acetate, and then the solvent was evaporated, therebyyielding the title compound (1.94 g) as a yellow solid crude product. ¹HNMR (400 MHz, DMSO-d₆) δ ppm; 2.05 (3H, s), 2.23 (3H, s), 3.91 (3H, s),7.89 (1H, s), 10.10 (1H, br s).(1e) 6-Methoxy-5-methyl-2-nitro-3-pyridinamine

The crude product (1.93 g) of N-(6-methoxy-5-methyl-2-nitro-3-pyridinyl)acetamide was dissolved in methanol (36 ml), 5N sodium hydroxidesolution (6 ml) was added, and the reaction mixture was stirred for 15minutes at room temperature. After water was added to the reactionsolution, it was extracted with ethyl acetate and dried over magnesiumsulfate, and the solvent was evaporated, thereby yielding the titlecompound (1.06 g, 5.79 mmol) as a yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ ppm; 2.15 (3H, s), 3.84 (3H, s), 7.25 (2H, br s), 7.34 (1H,s).(1f) 5-Methoxy-6-methyl-3H-imidazo[4,5-b]pyridine-2-thiol

6-Methoxy-5-methyl-2-nitro-3-pyridineamine (5.40 g, 29.5 mmol) wasdissolved in methanol (300 ml), 10% Pd-on-carbon powder (50% watercontent article) (2.73 g) was added, and the reaction mixture wasstirred under hydrogen atmosphere for 5 hours and 25 minutes. After thereaction was completed, the reaction mixture was filtered, carbonbisulfide (110 ml) was added, and stirred at room temperature for 65hours and 40 minutes under nitrogen atmosphere, and the solvent wasevaporated, thereby yielding the title compound (5.59 g, 28.6 mmol,97.1%) as a brown solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm; 2.16 (3H, s),3.86 (3H, s), 7.35 (1H, s), 12.46 (1H, br s), 12.88 (1H, br s).(1g)5-Methoxy-2-(((4-methoxy-3-methyl-2-pyridinyl)methyl)thio)-6-methyl-3H-imidazo[4,5-b]pyridine

A mixture of 5-methoxy-6-methyl-3H-imidazo[4,5-b]pyridine-2-thol (971mg, 5.0 mmol), 2-chloromethyl-4-methoxy-3-methylpyridine hydrochloridesalt (1.35 g, 6.5 mmol), sodium hydroxide (822 mg) and methanol (40 ml)was stirred overnight at room temperature under nitrogen atmosphere.After the reaction was completed, the solvent was evaporated by half,ammonium chloride solution was added thereto, and the reaction mixturewas extracted with chloroform (300 ml), dried over magnesium sulfate,and the solvent was evaporated, thereby yielding the crude product,which was then precipitated as a solid from a mixture of chloroform andether, and the title compound (1.06 g, 3.22 mmol, 64%) was obtained as apurple gray solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm; 2.19 (3H, s), 2.21(3H, s), 3.86 (3H, s), 3.90 (3H, s), 4.66 (2H, br s), 6.97 (1H, d, J=6Hz), 7.63 (1H, br s), 8.25 (1H, d, J=6 Hz).(1h)5-Methoxy-2-(((4-methoxy-3-methyl-2-pyridinyl)methyl)sulfinyl)-6-methyl-3H-imidazo[4,5-b]pyridine

5-Methoxy-2-(((4-methoxy-3-methyl-2-pyridinyl)methyl)thio)-6-methyl-3H-imidazo[4,5-b]pyridine(784 mg, 2.37 mmol) was dissolved in a mixture of methanol (6 ml) andtoluene (54 ml). Metachloroperbenzoic acid (566 mg) in a mixturesolution of methanol (3 ml) and toluene (3 ml) were added thereto at−40° C. under nitrogen flow, and the reaction mixture was stirred at −20to −40° C. for 2 hours. After the reaction was completed, a sodiumbicarbonate solution was added, and the organic layer was separated. Theaqueous layer was extracted with chloroform (40 ml), combined with theorganic layer and dried over sodium sulfate, the solvent was evaporatedand the residue was obtained which was then precipitated as a solid froma mixture of chloroform and ether, thereby yielding the title compound(654 mg, 1.89 mmol, 80%) as a purple gray solid. ¹H NMR (400 MHz,DMSO-d₆) δ ppm; 2.14 (3H, s), 2.25 (3H, s), 3.85 (3H, s), 3.94 (3H, s),4.72 (1H, d, J=14 Hz), 4.81 (1H, br d, J=14 Hz), 6.96 (1H, d, J=6 Hz),7.83 (1H, br s), 8.22 (1H, d, J=6 Hz).(1i)5-Methoxy-2-(((4-methoxy-3-methyl-2-pyridinyl)methyl)sulfinyl)-6-methyl-3H-imidazo[4,5-b]pyridinesodium salt

5-Methoxy-2-(((4-methoxy-3-methyl-2-pyridinyl)methyl)sulfinyl)-6-methyl-3H-imidazo[4,5-b]pyridine(654 mg, 1.89 mmol) was dissolved in ethanol (30 ml), a 1N sodiumhydroxide solution (1.89 ml, 1.89 mmol) was added thereto, and thereaction mixture was stirred for 30 minutes at room temperature. Theresidue which was obtained by evaporating the solvent was dissolved inethanol, and the solvent was evaporated again. The obtained residue wassuspended in ether, the solvent was evaporated, ether was added again toform a suspension, the solvent was evaporated thereby yielding the titlecompound (690 mg, 1.87 mmol, 99%) as a white solid. ¹H NMR (400 MHz,DMSO-d₆) δ ppm; 2.16 (3H, s), 2.19 (3H, s), 3.85 (3H, s), 3.86 (3H, s),4.39 (1H, d, J=13 Hz), 4.75 (1H, d, J=13 Hz), 6.94 (1H, d, J=6 Hz), 7.54(1H, s), 8.30 (1H, d, J=6 Hz).

Example 22-(((4-Methoxy-3-methyl-2-pyridinyl)methyl]sulfinyl)-6-methyl-5-(2,2,2-trifluoroethoxy)-3H-imidazo[4,5-b]pyridineSodium salt

(2a) 2-Chloro-3-methylpyridine 1-oxide

Into a mixture of 2-chloro-3-methylpyridine (12.8 g, 100 mmol), ureahydrogen peroxide addition compound ((NH₂)₂CO.H₂O₂, 19.8 g, 210 mmol)and dichloromethane (130 ml) was added dropwise anhydroustrifluoroacetic acid (28.2 ml, 200 mmol) at 0° C. under nitrogen flow,and the reaction mixture was stirred at 0° C. for 1 hour. Then, afterstirring for 30 minutes and elevating the reaction temperature to roomtemperature, an aqueous solution (200 ml) of sodium hydrosulfite (20 g)was added, and the reaction mixture was stirred for 15 minutes. 2Nhydrochloric acid (50 ml) was added and the mixture was extracted withdichloromethane (120 ml), and after washed with sodium bicarbonatesolution, the mixture was dried over magnesium sulfate and the solventwas evaporated, thereby yielding the title compound (9.00 g, 62.7 mmol,63%) as a pale yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm; 2.38 (3H,s), 7.29-7.37 (2H, m), 8.30-8.38 (1H, m).(2b) 2-chloro-5-methylpyridine-1-oxide

Into a mixture of 2-chloro-5-methylpyridine (27.4 g, 215 mmol), ureahydrogen peroxide addition compound (42.5 g, 452 mmol), dichloromethane(250 ml) was added dropwise anhydrous trifluoroacetic acid (60.7 ml and430 mmol) at 0° C., and the reaction mixture was stirred at 0° C. for 1hour. Then, after stirring for 45 minutes while elevating the reactiontemperature to room temperature, an aqueous solution (450 ml) of sodiumhydrosulfite (45 g) was added, and the reaction mixture was stirred for15 minutes. 0.5N hydrochloric acid (400 ml) was added and the mixturewas extracted with dichloromethane (400 ml), and after washed withsodium bicarbonate solution, the mixture was dried over magnesiumsulfate and the solvent was evaporated, thereby yielding the titlecompound (22.5 g, 157 mmol, 73%) as a beige solid. ¹H NMR (400 MHz,DMSO-d₆) δ ppm; 2.24 (3H, s), 7.16-7.23 (1H, m), 7.66 (1H, d, J=8 Hz),8.35 (1H, s).(2c) 2,6-Dichloro-3-methylpyridine

(Method 1)

2-Chloro-3-methylpyridine 1-oxide (9.00 g, 62.7 mmol) and triethylamine(10.4 ml, 75.2 mmol) were dissolved in dichloromethane (70 ml), and asolution of phosphorus oxychloride (7 ml, 75.3 mmol) in dichloromethane(40 ml) was added dropwise at 0° C. After stirring for 3 hours whileelevating reaction temperature to room temperature, the reaction mixturewas stirred under reflux for 1 hour. After the reaction was completed,water (30 ml) was added and the reaction mixture was neutralized with asodium hydroxide solution, and after extracted with dichloromethane (70ml), dried over magnesium sulfate. The solvent was evaporated andpurified by silica gel column chromatography (eluting solvent: ethylacetate/n-hexane=3/100), thereby yielding the title compound (3.47 g) asa white solid 10:3 mixture with 2,4-dichloro-3-methylpyridine.

(Method 2)

2-Chloro-5-methylpyridine 1-oxide (22.5 g, 157 mmol) and triethylamine(27.6 ml, 188 mmol) were dissolved in dichloromethane (160 ml), and thedichloromethane (80 ml) solution of phosphorus oxychloride (17.5 ml, 188mmol) was added dropwise at −10° C. After stirring at −10° C. to 0° C.for 2 hours, stirring was conducted for 1 hour and 35 minutes whileelevating reaction temperature to room temperature. After the reactionwas completed, water (60 ml) was added thereto and the mixture wasneutralized with a sodium hydroxide solution, and the separated organiclayer was washed with a saturated brine solution. The aqueous layer ofthe reaction solution was extracted with ethyl acetate, washed with asaturated brine solution, the organic layer was combined and dried overmagnesium sulfate. The solvent was evaporated and purified by silica gelcolumn chromatography (eluting solvent: ethyl acetate/n-hexane), therebyyielding the title compound (17.4 g) as a white solid 10:1.5 mixturewith 2,4-dichloro-5-methylpyridine. ¹H NMR (400 MHz, DMSO-d₆) δ ppm;2.33 (3H, s), 7.50 (1H, d, J=8 Hz), 7.89 (1H, d, J=8 Hz).(2d) 2,6-Dichloro-3-methyl-5-nitropyridine

Anhydrous trifluoromethanesulfonic acid (21.9 ml, 129 mmol) was droppedinto a mixture of tetramethyl ammonium nitrate (17.3 g, 127 mmol) anddichloromethane (60 ml) at 0° C. under nitrogen flow, and the reactionmixture was stirred for 1.5 hours while elevating to room temperature.After a 10:1.5 mixture (13.7 g) of 2,6-dichloro-3-methylpyridine and2,4-dichloro-5-methylpyridine in dichloromethane (20 ml) was added andstirred for 30 minutes at room temperature, the reaction mixture wasstirred under reflux for 48 hours. The reaction mixture was poured intoa saturated sodium bicarbonate solution, and extracted withdichloromethane (200 ml), and after washed with water, dried overmagnesium sulfate. The residue obtained by evaporating the solvent wastriturated with heptane, thereby yielding the title compound (6.55 g,31.6 mmol) as a pale brown solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm; 2.42(3H, s), 8.70 (1H, s).(2e) 6-Chloro-5-methyl-3-nitro-2-pyridinamine

A mixture of 2,6-dichloro-3-methyl-5-nitropyridine (10.41 g, 50.3 mmol),28% aqueous ammonia solution (17 ml, 0.25 mol), potassium carbonate(10.4 g, 75.5 mmol) and t-butanol (167 ml) was stirred overnight at 60°C. under nitrogen atmosphere. After stirring at room temperature for 3hours, a precipitate was filtered and then washed three times withwater, thereby yielding the title compound (4.25 g, 22.7 mmol, 45%) as ayellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm; 2.23 (3H, s), 8.04 (2H,br s), 8.39 (1H, s).(2f) 5-Methyl-3-nitro-6-(2,2,2-trifluoroethoxy)-2-pyridinamine

2,2,2-Trifluoroethanol (340 mg, 3.4 mmol) was dissolved in thetetrahydrofuran (10 ml), sodium hydride (60%) (120 mg, 3.0 mmol) wasadded thereto, and the reaction mixture was stirred for 30 minutes atroom temperature under nitrogen atmosphere. A solution of6-chloro-5-methyl-3-nitro-2-pyridineamine crude product (400 mg) intetrahydrofuran (10 ml) was dropped, and the reaction mixture wasstirred at room temperature for 2.5 days. Water was added to thereaction solution and extracted with ethyl acetate, and after washedwith a sodium bicarbonate solution, dried over magnesium sulfate. Theresidue obtained by evaporating the solvent was purified by silica gelcolumn chromatography (eluting solvent: ethyl acetate/n-hexane=15/85) toyield the title compound (225 mg, 0.90 mmol) as a yellow solid. ¹H NMR(400 MHz, DMSO-d₆) δ ppm; 2.07 (3H, s), 5.06 (2H, q, J=9 Hz), 8.05 (2H,br s), 8.24 (1H, s).(2g)6-Methyl-5-(2,2,2-trifluoroethoxy)-3H-imidazo[4,5-b]pyridine-2-thiol

5-Methyl-3-nitro-6-(2,2,2-trifluoroethoxy)-2-pyridineamine (225 mg, 0.90mmol) was dissolved in methanol (10 ml), 10% Pd-on-carbon powder (50%water content article) (110 mg) was added thereto, and the reactionmixture was stirred under hydrogen atmosphere for 2 hours and 25minutes. After the reaction was completed, the reaction mixture wasfiltered through celite, carbon bisulfide (3 ml) was added and stirredat room temperature under nitrogen atmosphere for 2.5 days, and thesolvent was then evaporated, thereby yielding the title compound (238mg, 0.90 mmol) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm; 2.20(3H, s), 4.94 (2H, q, J=9 Hz), 7.44 (1H, s), 12.60 (1H, br s), 13.00(1H, br s).(2h)2-(((4-Methoxy-3-methyl-2-pyridinyl)methyl)thio)-6-methyl-5-(2,2,2-trifluoroethoxy)-3H-imidazo[4,5-b]pyridine

6-Methyl-5-(2,2,2-trifluoroethoxy)-3H-imidazo[4,5-b]pyridine-2-thol (238mg, 0.90 mmol) and 2-chloromethyl-4-methoxy-3-methylpyridinehydrochloride salt (243 mg, 1.17 mmol) was dissolved in methanol (20ml), sodium hydroxide (218 mg, 5.45 mmol) was added thereto, and themixture was stirred at room temperature overnight. An ammonium chloridesolution was added, and the mixture was extracted with chloroform (100ml), and dried over magnesium sulfate. The residue obtained byevaporating the solvent was purified by silica gel column chromatography(eluting solvent: ethyl acetate/n-hexane=1/1-4/1) to yield the titlecompound (196 mg, 0.49 mmol, 54%) as a white solid. ¹H NMR (400 MHz,DMSO-d₆) δ ppm; 2.19 (3H, s), 2.24 (3H, s), 3.85 (3H, s), 4.67 (2H, s),4.99 (2H, q, J=9 Hz), 6.96 (1H, d, J=6 Hz), 7.72 (1H, br s), 8.24 (1H,d, J=6 Hz).(2i)2-(((4-Methoxy-3-methyl-2-pyridinyl)methyl)sulfinyl)-6-methyl-5-(2,2,2-trifluoroethoxy)-3H-imidazo[4,5-b]pyridine

2-(((4-Methoxy-3-methyl-2-pyridinyl)methyl)thio)-6-methyl-5-(2,2,2-trifluoroethoxy)-3H-imidazo[4,5-b]pyridine(270 mg, 0.68 mmol) was dissolved in a mixture of methanol (2 ml) andtoluene (18 ml), and a solution of metachloroperbenzoic acid (162 mg) ina mixture of methanol (0.5 ml) of toluene (0.5 ml) were added dropwiseat −40° C. under nitrogen flow. After stirred at −20° C. to −40° C. for2 hours, a sodium bicarbonate solution was added, the mixture wasextracted with chloroform (30 ml), and dried over sodium sulfate. Thesolvent was evaporated, and the solid was precipitated from a mixture ofchloroform and n-hexane to yield the title compound (263 mg, 0.63 mmol,93%) as a purple gray solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm; 2.14 (3H,s), 2.28 (3H, s), 3.85 (3H, s), 4.68 (1H, d, J=14 Hz), 4.80 (1H, d, J=14Hz), 5.04 (2H, q, J=9 Hz), 6.96 (1H, d, J=6 Hz), 7.88 (1H, br s), 8.22(1H, d, J=6 Hz).(2j)2-(((4-Methoxy-3-methyl-2-pyridinyl)methyl)sulfinyl)-6-methyl-5-(2,2,2-trifluoroethoxy)-3H-imidazo[4,5-b]pyridinesodium salt

2-(((4-Methoxy-3-methyl-2-pyridinyl)methyl)sulfinyl)-6-methyl-5-(2,2,2-trifluoroethoxy)-3H-imidazo[4,5-b]pyridine(263 mg, 0.64 mmol) was suspended in ethanol (30 ml), 1N sodiumhydroxide solution (635 μl, 0.64 mmol) was added thereto, and thereaction mixture was stirred for 30 minutes at room temperature. Afterthe solvent was evaporated, ethanol was added and evaporation wasconducted again. Ether was added and evaporation was conducted. Thisoperation was repeated twice, thereby yielding the title compound (272mg, 0.62 mmol, 98%) as a purple gray solid. ¹H NMR (400 MHz, DMSO-d₆) δppm; 2.16 (3H, s), 2.22 (3H, s), 3.84 (3H, s), 4.38 (1H, d, J=13 Hz),4.78 (1H, d, J=13 Hz), 4.97 (2H, q, J=9 Hz), 6.92 (1H, d, J=6 Hz), 7.61(1H, s), 8.28 (1H, d, J=6 Hz).

Example 35-(2,2-Difluoroethoxy)-2-(((4-methoxy-3-methyl-2-pyridinyl)methyl)sulfinyl)-6-methyl-3H-imidazo[4,5-b]pyridineSodium salt

(3a) 6-(2,2-difluoroethoxy)-5-methyl-3-nitro-2-pyridineamine

2,2-Difluoro ethanol (418 mg, 5.1 mmol) was dissolved in tetrahydrofuran(15 ml), sodium hydride (60%) (180 mg, 4.5 mmol) was added thereto undernitrogen atmosphere, and the reaction mixture was stirred for 30 minutesat room temperature. A solution of6-chloro-5-methyl-3-nitro-2-pyridineamine (600 mg, 3.20 mmol) intetrahydrofuran (15 ml) was dropped, and the mixture was stirred at roomtemperature overnight. Water was added to the reaction solution andextracted with ethyl acetate, and after washed with sodium bicarbonatesolution, dried over magnesium sulfate. The residue obtained byevaporating the solvent was triturated with n-hexane to yield the titlecompound (685 mg, 3.1 mmol, 96%) as an orange solid. ¹H NMR (400 MHz,DMSO-d₆) δ ppm; 2.05 (3H, s), 4.56-4.69 (2H, m), 6.29-6.60 (1H, m), 8.03(2H, br s), 8.19 (1H, s).(3b) 5-(2,2-Difluoroethoxy)-6-methyl-3H-imidazo[4,5-b]pyridine-2-thiol

6-(2,2-Difluoroethoxy)-5-methyl-3-nitro-2-pyridineamine (685 mg, 3.07mmol) was dissolved in methanol (30 ml), 10% Pd-on-carbon powder (50%water content article) (300 mg) was added thereto, and the reactionmixture was stirred under hydrogen atmosphere for 2 hours and 30minutes. After the reaction was completed, the mixture was filteredthrough celite, carbon bisulfide (7 ml) was added, and the mixture wasstirred at room temperature under nitrogen atmosphere for 2.5 days.Thereafter, the solvent was evaporated to yield the title compound (700mg, 2.85 mmol) as a purple gray solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm;2.18 (3H, s), 4.46-4.59 (2H, m), 6.23-6.54 (1H, m), 7.39 (1H, s), 12.51(1H, br s), 12.92 (1H, br s).(3c)5-(2,2-Difluoroethoxy)-2-(((4-methoxy-3-methyl-2-pyridinyl)methyl)thio)-6-methyl-3H-imidazo[4,5-b]pyridine

5-(2,2-Difluoroethoxy)-6-methyl-3H-imidazo[4,5-b]pyridine-2-thol (700mg, 2.85 mmol) and 2-chloromethyl-4-methoxy-3-methylpyridinehydrochloride salt (832 mg, 4.0 mmol) was dissolved in methanol (30 ml),sodium hydroxide (561 mg, 14.0 mmol) was added thereto, and the mixturewas stirred overnight at room temperature under nitrogen atmosphere. Anammonium chloride solution was added to the reaction solution, themixture was extracted with ethyl acetate and chloroform (100 ml), andthen dried over magnesium sulfate. The residue obtained by evaporatingthe solvent was purified by silica gel column chromatography (NH silicagel, eluting solvent: ethyl acetate/n-hexane=1/1-1/0), and trituratedwith ethanol, thereby yielding the title compound (360 mg, 0.95 mmol,33%) as a beige solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm; 2.19 (3H, s),2.24 (3H, s), 3.85 (3H, s), 4.53-4.64 (2H, m), 4.67 (2H, s), 6.26-6.57(1H, m), 6.96 (1H, d, J=6 Hz), 7.68 (1H, br s), 8.24 (1H, d, J=6 Hz).(3d)5-(2,2-Difluoroethoxy)-2-(((4-methoxy-3-methyl-2-pyridinyl)methyl)sulfinyl)-6-methyl-3H-imidazo[4,5-b]pyridine

5-(2,2-Difluoroethoxy)-2-(((4-methoxy-3-methyl-2-pyridinyl)methyl)thio)-6-methyl-3H-imidazo[4,5-b]pyridine(150 mg, 0.39 mmol) was dissolved in a mixture of methanol (1.5 ml) andtoluene (13.5 ml) and a solution of metachloroperbenzoic acid (94 mg) ina mixture of methanol (0.5 ml) and toluene (0.5 ml) were added dropwisethereto at −40° C. under nitrogen flow.

After stirred at −20° C. to −40° C. for 2 hours, a sodium bicarbonatesolution was added, the organic layer was separated, and the aqueouslayer was extracted with chloroform (20 ml), and the organic layer wascombined and dried over sodium sulfate. The solvent was evaporated, andthe solid was then precipitated from a mixture of chloroform, ether andn-hexane, thereby yielding the title compound (134 mg, 0.34 mmol, 86%)as a pale blue solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm; 2.13 (3H, s),2.28 (3H, s), 3.85 (3H, s), 4.56-4.69 (2H, m), 4.72 (1H, d, J=14 Hz),4.79 (1H, d, J=14 Hz), 6.28-6.60 (1H, m), 6.95 (1H, d, J=6 Hz), 7.88(1H, br s), 8.20 (1H, d, J=6 Hz).(3e)5-(2,2-Difluoroethoxy)-2-(((4-methoxy-3-methyl-2-pyridinyl)methyl)sulfinyl)-6-methyl-3H-imidazo[4,5-b]pyridinesodium salt

5-(2,2-Difluoroethoxy)-2-(((4-methoxy-3-methyl-2-pyridinyl)methyl)sulfinyl]-6-methyl-3H-imidazo[4,5-b]pyridine(286 mg, 0.72 mmol) was made to suspend in ethanol (10 ml). The mixtureof a 1N sodium hydroxide solution (720 μl, 0.72 mmol) and ethanol (3 ml)was added, and the reaction mixture was stirred for 20 minutes at roomtemperature. After the solvent was evaporated, ethanol was added andevaporation was conducted again, ether was added and evaporation wasconducted. This operation was repeated twice, thereby yielding the titlecompound (277 mg, 0.66 mmol, 92%) as a beige solid. ¹H NMR (400 MHz,DMSO-d₆) δ ppm; 2.16 (3H, s), 2.21 (3H, s), 3.85 (3H, s), 4.38 (1H, d,J=13 Hz), 4.56 (2H, dt, J=4, 15 Hz), 4.78 (1H, d, J=13 Hz), 6.42 (1H,tt, J=4, 55 Hz), 6.94 (1H, d, J=6 Hz), 7.60 (1H, s), 8.30 (1H, d, J=6Hz).

Example 4 Optical isomers of5-methoxy-2-(((4-methoxy-3-methyl-2-pyridinyl)methyl)sulfinyl)-6-methyl-3H-imidazo[4,5-b]pyridine

5-Methoxy-2-(((4-methoxy-3-methyl-2-pyridinyl)methyl)sulfinyl]-6-methyl-3H-imidazo[4,5-b]pyridine(racemate) (360 mg) was prepared into a solution containing 3-4.5 mg ofthe racemate per ml of ethanol/n-hexane=3/2 and fractionated by HPLC(column: CHIRALPAK AD-H 2 cmφ×25 cm (Daicel Chemical Ind., Ltd.),Temperature: about 22° C., Mobile phase: ethanol/n-hexane=3/2, and Flowrate: 9 ml/min, Detection wavelength: 254 nm, 15 mg-22.5 mg/5 mlinjected per time). Fractions of an optical isomer having longerretention time and of an optical isomer having shorter retention timewere collected, respectively, and were condensed. The title compoundhaving shorter retention time (128 mg, 0.37 mmol) and the title compoundhaving longer retention time (116 mg, 0.33 mmol) were thus obtained asbeige solids, respectively. Title compound having shorter retentiontime: ¹H NMR (400 MHz, DMSO-d₆) δ ppm; 2.14 (3H, s), 2.25 (3H, s), 3.85(3H, s), 3.94 (3H, s), 4.71 (1H, d, J=14 Hz), 4.81 (1H, br d, J=14 Hz),6.96 (1H, d, J=6 Hz), 7.82 (1H, br s), 8.22 (1H, d, J=6 Hz). Titlecompound having longer retention time: ¹H NMR (400 MHz, DMSO-d₆) δ ppm;2.14 (3H, s), 2.25 (3H, s), 3.85 (3H, s), 3.94 (3H, s), 4.71 (1H, d,J=14 Hz), 4.81 (1H, br d, J=14 Hz), 6.96 (1H, d, J=6 Hz), 7.82 (1H, brs), 8.22 (1H, d, J=6 Hz).

Example 5 Optical isomers of5-(2,2-difluoroethoxy)-2-(((4-methoxy-3-methyl-2-pyridinyl)methyl)sulfinyl)-6-methyl-3H-imidazo[4,5-b]pyridine

5-(2,2-Difluoroethoxy)-2-(((4-methoxy-3-methyl-2-pyridinyl)methyl)sulfinyl)-6-methyl-3H-imidazo[4,5-b]pyridine(racemate) (350 mg) was prepared into a solution containing 5 mg of theracemate per ml of ethanol/n-hexane=1/4 (0.1% diethylamine content) andfractionated by HPLC(column: CHIRALPAK AD-H 2 cmφ×25 cm (Daicel ChemicalInd., Ltd.), Temperature: about 22° C., Mobilephase:ethanol/n-hexane=1/4 (0.1% diethylamine content), Flow rate: 9ml/min, Detection wavelength: 254 nm, 20 mg/4 ml were injected pertime). Fractions of an optical isomer having longer retention time andof an optical isomer having shorter retention time were collected,respectively, and were condensed, thereby yielding the title compoundhaving shorter retention time (125 mg, 0.32 mmol) and the title compoundhaving longer retention time (107 mg, 0.27 mmol) as beige color solids,respectively. Title compound having shorter retention time: ¹H NMR (400MHz, DMSO-d₆) δ ppm; 2.14 (3H, s), 2.27 (3H, s), 3.85 (3H, s), 4.56-4.69(2H, m), 4.68 (1H, d, J=14 Hz), 4.79 (1H, d, J=14 Hz), 6.28-6.60 (1H,m), 6.95 (1H, d, J=6 Hz), 7.84 (1H, br s), 8.21 (1H, d, J=6 Hz). Titlecompound having longer retention time: ¹H NMR (400 MHz, DMSO-d₆) δ ppm;2.14 (3H, s), 2.27 (3H, s), 3.85 (3H, s), 4.56-4.69 (2H, m), 4.68 (1H,d, J=14 Hz), 4.80 (1H, d, J=14 Hz), 6.28-6.60 (1H, m), 6.95 (1H, d, J=6Hz), 7.84 (1H, br s), 8.21 (1H, d, J=6 Hz).

Example 6 Sodium salt of an optical isomer having shorter retention timeof5-methoxy-2-(((4-methoxy-3-methyl-2-pyridinyl)methyl)sulfinyl)-6-methyl-3H-imidazo[4,5-b]pyridine

5-Methoxy-2-(((4-methoxy-3-methyl-2-pyridinyl)methyl)sulfinyl)-6-methyl-3H-imidazo[4,5-b]pyridinein the form of an optical isomer having shorter retention time (124 mg,0.36 mmol) was dissolved in ethanol (20 ml) and a mixed solution of 1Nsodium hydroxide solution (0.36 ml, 0.36 mmol) and ethanol (2 ml) wasadded thereto and the reaction mixture was stirred for 30 minutes atroom temperature. The residue which was obtained by evaporating thesolvent was dissolved in ethanol, and the solvent was evaporated again.Ether was added to the resulting residue to form a suspension, ether wasevaporated, and ether was added again to form a suspension and thesolvent was evaporated, thereby yielding the title compound (133 mg,0.36 mmol) as a beige solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm; 2.16 (3H,s), 2.18 (3H, s), 3.85 (3H, s), 3.86 (3H, s), 4.36 (1H, d, J=13 Hz),4.80 (1H, d, J=13 Hz), 6.92 (1H, d, J=6 Hz), 7.52 (1H, s), 8.28 (1H, d,J=6 Hz).

Example 7 Sodium salt of an optical isomer having longer retention timeof5-methoxy-2-(((4-methoxy-3-methyl-2-pyridinyl)methyl)sulfinyl)-6-methyl-3H-imidazo[4,5-b]pyridine

5-Methoxy-2-(((4-methoxy-3-methyl-2-pyridinyl)methyl)sulfinyl)-6-methyl-3H-imidazo[4,5-b]pyridinein the form of an optical isomer having longer retention time (83 mg,0.24 mmol) was dissolved in ethanol (15 ml) and a mixed solution of 1Nsodium hydroxide solution (0.24 ml, 0.24 mmol) and ethanol (2 ml) wasadded, and the reaction mixture was stirred for 30 minutes at roomtemperature. The residue which was obtained by evaporating the solventwas dissolved in ethanol, and the solvent was evaporated again. Etherwas added to the resulting residue to form a suspension, ether wasevaporated, and ether was added again to form a suspension and thesolvent was evaporated, thereby yielding the title compound (88 mg, 0.24mmol) as a beige solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm; 2.16 (3H, s),2.18 (3H, s), 3.84 (3H, s), 3.85 (3H, s), 4.36 (1H, d, J=13 Hz), 4.80(1H, d, J=13 Hz), 6.92 (1H, d, J=6 Hz), 7.51 (1H, s), 8.28 (1H, d, J=6Hz).

Example 8 Sodium salt of an optical isomer having shorter retention timeof5-(2,2-difluoroethoxy)-2-(((4-methoxy-3-methyl-2-pyridinyl)methyl)sulfinyl)-6-methyl-3H-imidazo[4,5-b]pyridine

5-(2,2-Difluoroethoxy)-2-(((4-methoxy-3-methyl-2-pyridinyl)methyl)sulfinyl)-6-methyl-3H-imidazo[4,5-b]pyridinein the form of an optical isomer having shorter retention time (125 mg,0.32 mmol) was dissolved in ethanol (20 ml) and a mixed solution of 1Nsodium hydroxide solution (0.32 ml, 0.32 mmol) and ethanol (5 ml) wereadded, and the reaction mixture was stirred for 30 minutes at roomtemperature. The residue which was obtained by evaporating the solventwas dissolved in ethanol, and the solvent was evaporated again. Etherwas added to the resulting residue to form a suspension, and the solventwas evaporated, thereby yielding the title compound (122 mg, 0.29 mmol)as a beige solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm; 2.16 (3H, s), 2.21(3H, s), 3.84 (3H, s), 4.37 (1H, d, J=13 Hz), 4.55 (2H, dt, J=4, 15 Hz),4.78 (1H, d, J=13 Hz), 6.42 (1H, tt, J=4, 55 Hz), 6.93 (1H, d, J=6 Hz),7.58 (1H, s), 8.28 (1H, d, J=6 Hz).

Example 9 Sodium salt of an optical isomer having longer retention timeof5-(2,2-difluoroethoxy)-2-(((4-methoxy-3-methyl-2-pyridinyl)methyl)sulfinyl)-6-methyl-3H-imidazo[4,5-b]pyridine

5-(2,2-Difluoroethoxy)-2-(((4-methoxy-3-methyl-2-pyridinyl)methyl)sulfinyl)-6-methyl-3H-imidazo[4,5-b]pyridinein the form of an optical isomer having longer retention time (107 mg,0.27 mmol) was dissolved in ethanol (20 ml) and a mixed solution of 1Nsodium hydroxide solution (0.27 ml, 0.27 mmol) and ethanol (5 ml) wereadded, and the reaction mixture was stirred for 30 minutes at roomtemperature. The residue which was obtained by evaporating the solventwas dissolved in ethanol, and the solvent was evaporated again. Etherwas added to the resulting residue to form a suspension, and the solventwas evaporated, thereby yielding the title compound (99 mg, 0.24 mmol)as a beige solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm; 2.16 (3H, s), 2.21(3H, s), 3.84 (3H, s), 4.38 (1H, d, J=13 Hz), 4.55 (2H, dt, J=4, 15 Hz),4.79 (1H, d, J=13 Hz), 6.41 (1H, tt, J=4, 55 Hz), 6.92 (1H, d, J=6 Hz),7.59 (1H, s), 8.28 (1H, d, J=6 Hz).

Example 10 Sodium salt of5-(4-fluorophenoxy)-2-(((4-methoxy-3-methyl-2-pyridinyl)methyl)sulfinyl)-3H-imidazo[4,5-b]pyridine

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 2.15 (3H, s), 3.84 (3H, s), 4.40 (1H,d, J=13 Hz), 4.70 (1H, d, J=13 Hz), 6.59 (1H, d, J=8 Hz), 6.94 (1H, d,J=6 Hz), 6.93-7.11 (2H, m), 7.16-7.21 (2H, m), 7.84 (1H, d, J=8 Hz),8.29 (1H, d, J=6 Hz)

Example 11 Sodium salt of5-(3-fluorophenoxy)-2-(((4-methoxy-3-methyl-2-pyridinyl)methyl)sulfinyl)-3H-imidazo[4,5-b]pyridine

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 2.14 (3H, s), 3.83 (3H, s), 4.41 (1H,d, J=13 Hz), 4.70 (1H, d, J=13 Hz), 6.63 (1H, d, J=8 Hz), 6.86-6.94 (4H,m), 7.37 (1H, q, J=8 Hz), 7.86 (1H, d, J=8 Hz), 8.29 (1H, d, J=6 Hz)

Example 12 Sodium salt of2-(((4-methoxy-3-methyl-2-pyridinyl)methyl)sulfinyl)5-(4-methoxyphenoxy)-6-methyl-3H-imidazo[4,5-b]pyridine

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 2.14 (3H, s), 2.30 (3H, s), 3.74 (3H,s), 3.84 (3H, s), 4.35 (1H, d, J=13 Hz), 4.74 (1H, d, J=13 Hz),6.86-6.97 (5H, m), 7.65 (1H, s), 8.28 (1H, d, J=6 Hz)

Example 13

Sodium salt of2-(((4-methoxy-3-methyl-2-pyridinyl)methyl)sulfinyl)5-(2-phenoxyethoxy)-3H-imidazo[4,5-b]pyridine

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 2.18 (3H, s), 3.85 (3H, s), 4.30-4.36(2H, m), 4.39 (1H, d, J=13 Hz), 4.55-4.62 (2H, m), 4.80 (1H, d, J=13Hz), 6.38 (1H, d, J=8 Hz), 6.92-6.97 (2H, m), 6.98-7.03 (2H, m),7.27-7.33 (2H, m), 7.71 (1H, d, J=8 Hz), 8.30 (1H, d, J=6 Hz).

Example 14 Sodium salt of5-(2-(4-fluorophenyl)ethoxy)-2-(((4-methoxy-3-methyl-2-pyridinyl)methyl)sulfinyl)-3H-imidazo[4,5-b]pyridine

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 2.17 (3H, s), 3.04 (2H, t, J=7 Hz),3.85 (3H, s), 4.38 (1H, d, J=13 Hz), 4.44 (2H, t, J=7 Hz), 4.78 (1H, d,J=13 Hz), 6.31 (1H, d, J=8 Hz), 6.94 (1H, d, J=6 Hz), 7.10-7.17 (2H, m),7.33-7.39 (2H, m), 7.68 (1H, d, J=8 Hz), 8.30 (1H, d, J=6 Hz).

Example 15 Sodium salt of2-(((4-methoxy-3-methyl-2-pyridinyl)methyl)sulfinyl)-5-(2-phenylpropoxy)-3H-imidazo[4,5-b]pyridine

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 1.30 (3H, d, J=7 Hz), 2.15 (3H, s),3.18-3.28 (1H, m), 3.38 (3H, s), 4.25-4.40 (2H, m), 4.37 (1H, d, J=13Hz), 4.75 (1H, d, J=13 Hz), 6.27 (1H, d, J=8 Hz), 6.92 (1H, d, J=6 Hz),7.17-7.23 (1H, m), 7.28-7.34 (4H, m), 7.64 (1H, d, J=8 Hz), 8.28 (1H, d,J=6 Hz).

Example 16 Sodium salt of5-(2,2-difluoroethoxy)-6-ethyl-2-(((4-methoxy-3-methyl-2-pyridinyl)methyl)sulfinyl)-3H-imidazo[4,5-b]pyridine

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 1.17 (3H, t, J=7 Hz), 2.17 (3H, s),2.60 (2H, q, J=7 Hz), 3.84 (3H, s), 4.37 (1H, d, J=13 Hz), 4.51-4.60(2H, m), 4.76 (1H, d, J=13 Hz), 6.41 (1H, tt, J=4, 55 Hz), 6.93 (1H, d,J=6 Hz), 7.58 (1H, s), 8.28 (1H, d, J=6 Hz)

Example 17 Sodium salt of5-(2,2-difluoroethoxy)-2-(((4-methoxy-3-methyl-2-pyridinyl)methyl)sulfinyl)-6-propyl-3H-imidazo[4,5-b]pyridine

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 0.90 (3H, t, J=7 Hz), 1.59 (2H, sex,J=7 Hz), 2.17 (3H, s), 2.57 (2H, t, J=7 Hz), 3.84 (3H, s), 4.37 (1H, d,J=13 Hz), 4.55 (2H, dt, J=4, 15 Hz), 4.76 (1H, d, J=13 Hz), 6.40 (1H,tt, J=4, 55 Hz), 6.93 (1H, d, J=6 Hz), 7.56 (1H, s), 8.29 (1H, d, J=6Hz).

Example 18 Sodium salt of2-(((3-ethyl-4-methoxy-2-pyridinyl)methyl)sulfinyl)-(5-methoxy-6-methyl-3H-imidazo[4,5-b]pyridine

¹H NMR (400 MHz, DMSO-d₆)δppm; 1.07 (3H, t, J=8 Hz), 2.18 (3H, s),2.60-2.83 (2H, m), 3.86 (6H, s), 4.33 (1H, d, J=13 Hz), 4.76 (1H, d,J=13 Hz), 6.96 (1H, d, J=6 Hz), 7.54 (1H,s), 8.32 (1H, d, J=6 Hz).

Example 19 Sodium salt of5-(2-butynyloxy)-2-(((4-methoxy-3-methyl-2-pyridinyl)methyl)sulfinyl)-6-methyl-3H-imidazo[4,5-b]pyridine

¹H NMR (400 MHz, DMSO-d₆)δppm; 1.03 (3H, t, J=2 Hz), 2.17 (3H, s), 2.19(3H, s), 3.85 (3H, s), 4.36 (1H, d, J=13 Hz), 4.80 (1H, d, J=13 Hz),4.93 (2H, q, J=2 Hz), 6.93 (1H, d, J=6 Hz), 7.55 (1H, s), 8.29 (1H, d,J=6 Hz).

Example 202-[[(4-Methoxy-3-methyl-2-pyridinyl)methyl]sulfinyl]-5-(3-pentynyloxy)-3H-imidazo[4,5-b]pyridinesodium salt

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 1.76 (3H, t, J=2 Hz), 2.16 (3H, s),2.52-2.62 (2H, m), 3.84 (3H, s), 4.28 (2H, t, J=7 Hz), 4.38 (1H, d, J=13Hz), 4.75 (1H, d, J=13 Hz), 6.32 (1H, d, J=8 Hz), 6.93 (1H, d, J=6 Hz),7.67 (1H, d, J=8 Hz), 8.28 (1H, d, J=6 Hz).

Example 215-Ethoxy-2-[[(4-methoxy-3-methyl-2-pyridinyl)methyl]sulfinyl]-6-methyl-3H-imidazo[4,5-b]pyridinesodium salt

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 1.34 (3H, t, J=7 Hz), 2.16 (3H, s),2.17 (3H, s), 3.85 (3H, s), 4.31 (2H, q, J=7 Hz), 4.37 (1H, d, J=13 Hz),4.78 (1H, d, J=13 Hz), 6.94 (1H, d, J=6 Hz), 7.52 (1H,s), 8.30 (1H, d,J=6 Hz).

Example 225-Isopropoxy-2-[[(4-methoxy-3-methyl-2-pyridinyl)methyl]sulfinyl]-6-methyl-3H-imidazo[4,5-b]pyridinesodium salt

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 1.29 (6H, d, J=6 Hz), 2.13 (3H, s),2.15 (3H, s), 3.83 (3H, s), 4.35 (1H, d, J=13 Hz), 4.77 (1H, d, J=13Hz), 5.27 (1H, hept, J=6 Hz), 6.92 (1H, d, J=6 Hz), 7.49 (1H, s), 8.28(1H, d, J=6 Hz).

Example 235-(Cyclopropylmethoxy)-2-[[(4-methoxy-3-methyl-2-pyridinyl)methyl]sulfinyl]-6-methyl-3H-imidazo[4,5-b]pyridinesodium salt

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 0.32-0.36 (2H, m), 0.51-0.56 (2H, m),1.24-1.34 (1H, m), 2.16 (3H, s), 2.20 (3H, s), 3.84 (3H, s), 4.12 (2H,d, J=7 Hz), 4.38 (1H, d, J=13 Hz), 4.80 (1H, d, J=13 Hz), 6.93 (1H, d,J=6 Hz), 7.53 (1H,s), 8.29 (1H, d, J=6 Hz).

Example 245-(2-Butynyloxy)-2-[[(4-methoxy-3-methyl-2-pyridinyl)methyl]sulfinyl]-3H-imidazo[4,5-b]pyridinesodium salt

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 1.81 (3H, t, J=2 Hz), 2.15 (3H, s),3.83 (3H, s), 4.36 (1H, d, J=13 Hz), 4.76 (1H, d, J=13 Hz), 4.85-4.90(2H, m), 6.34 (1H, d, J=8 Hz), 6.93 (1H, d, J=6 Hz), 7.69 (1H, d, J=8Hz), 8.28 (1H, d, J=6 Hz).

Example 252-[[(4-Methoxy-3-methyl-2-pyridinyl)methyl]sulfinyl]-5-methoxy-6-methyl-3H-imidazo[4,5-b]pyridinesodium salt

¹H NMR (400 MHz, DMSO-d₆)δ ppm; 1.36 (3H, t, J=7 Hz), 2.16 (3H, s), 2.18(3H, s), 3.86 (3H, s), 4.10 (2H, q, J=7 Hz), 4.37 (1H, d, J=13 Hz), 4.78(1H, d, J=13 Hz), 6.91 (1H, d, J=6 Hz), 7.53 (1H,s), 8.27 (1H, d, J=6Hz).

Example 262-[[(4-Methoxy-3-methyl-2-pyridinyl)methyl]sulfinyl]-6-methyl-5-(2-fluoroethoxy)-3H-imidazo[4,5-b]pyridinesodium salt

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 2.16 (3H, s), 2.20 (3H, s), 3.84 (3H,s), 4.37 (1H, d, J=13 Hz), 4.46-4.50 (1H, m), 4.54-4.58 (1H, m),4.70-4.74 (1H, m), 4.79 (1H, d, J=13 Hz), 4.82-4.86 (1H, m), 6.93 (1H,d, J=5 Hz), 7.56 (1H, s), 8.29 (1H, d, J=5 Hz).

Example 272-[[(4-Methoxy-3-methyl-2-pyridinyl)methyl]sulfinyl]-6-methyl-5-propoxy-3H-imidazo[4,5-b]pyridinesodium salt

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 1.00 (3H, t, J=7 Hz), 1.71-1.79 (2H,m), 2.16 (3H, s), 2.18 (3H, s), 3.84 (3H, s), 4.22 (2H, t, J=7 Hz), 4.37(1H, d, J=13 Hz), 4.80 (1H, d, J=13 Hz), 6.93 (1H, d, J=6 Hz), 7.52 (1H,s), 8.29 (1H, d, J=6 Hz).

Example 285-Isobutoxy-2-[[(4-methoxy-3-methyl-2-pyridinyl)methyl]sulfinyl]-6-methyl-3H-imidazo[4,5-b]pyridinesodium salt

¹H NMR (400 MHz, DMSO-d₆)δ ppm; 1.01 (6H, d, J=7 Hz), 2.01-2.12 (1H, m),2.16 (3H, s), 2.19 (3H, s), 3.85 (3H, s), 4.04 (2H, d, J=7 Hz), 4.37(1H, d, J=13 Hz), 4.81 (1H, d, J=13 Hz), 6.93 (1H, d, J=5 Hz), 7.52 (1H,d, J=1 Hz), 8.29 (1H, d, J=5 Hz).

Example 295-(Cyclohexyloxy)-2-[[(4-methoxy-3-methyl-2-pyridinyl)methyl]sulfinyl]-6-methyl-3H-imidazo[4,5-b]pyridinesodium salt

¹H NMR (400 MHz, DMSO-d₆)δ ppm; 1.29-1.59 (6H, m), 1.70-1.79 (2H, m),1.91-2.00 (2H, m), 2.17 (3H, s), 2.17 (3H, d, J=1 Hz), 3.85 (6H, s),4.38 (1H, d, J=13 Hz), 4.81 (1H, d, J=13 Hz), 5.04-5.12 (1H, m), 6.93(1H, d, J=6 Hz), 7.53 (1H, d, J=1 Hz), 8.29 (1H, d, J=6 Hz).

Preparation Example 1 6-Methoxy-3-nitro-2-pyridineamine

A solution of 2-chloro-6-methoxy-3-nitropyridine (25.3 g, 0.134 mol) anda concentrated aqueous ammonia solution (70 ml) in N,N-dimethylformamide(200 ml) was stirred at 70° C. for 4 hours and 15 minutes. The reactionmixture was cooled to room temperature and then diluted with water. Theresulted precipitate was collected by filtration to yield the titlecompound (16.8 g, 99.2 mmol, 74.0%) as a yellow solid. ¹H NMR (400 MHz,DMSO-d₆)δppm; 3.90 (3H, s), 6.16 (1H, d, J=9 Hz), 8.16 (2H, br s), 8.26(1H, d, J=9 Hz).

Preparation Example 2 5-Iodo-6-methoxy-3-nitro-2-pyridineamine

A suspension of 6-methoxy-3-nitro-2-pyridineamine (14.6 g, 86.4 mmol)and N-iodosuccinimide (29.2 g, 130 mmol) in acetic acid (280 ml) wasstirred at room temperature for 21 hours and 30 minutes. The reactionmixture was concentrated and the residue was dissolved in ethyl acetateand 0.5N sodium hydroxide. The ethyl acetate layer was washed with asaturated sodium bicarbonate solution and a saturated brine solution,dried over anhydrous sodium sulfate, and concentrated. The residue wassuspended in hexane, and a resulted precipitate was filtered and washedwith hexane, thereby yielding the title compound (25.2 g, 85.5 mmol,98.9%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆)δppm; 3.91 (3H, s),8.20 (2H, br s), 8.54 (1H, s).

Preparation Example 3 6-Methoxy-5-methyl-3-nitro-2-pyridineamine

A mixture of 5-iodo-6-methoxy-3-nitro-2-pyridineamine (1.03 g, 3.49mmol), trimethylboroxin (456 mg, 3.63 mmol), cesium carbonate (3.56 g,10.9 mmol), tetrakis(triphenylphosphine)palladium(0) (412 mg, 0.357mmol) and N,N-dimethylformamide (10 ml) was stirred at 90° C. undernitrogen atmosphere. After 2 hours and 30 minutes, trimethylboroxin (500μl, 3.58 mmol) was added, and the reaction mixture was further stirredunder the same conditions for 5 hours and 30 minutes. The reactionmixture was cooled to room temperature and then diluted with ethylacetate and water. Insoluble substance was filtered off, the organiclayer of the filtrate was washed 3 times with a saturation ammoniumchloride solution, dried over anhydrous sodium sulfate, filtered andconcentrated. The residue was purified by silica gel columnchromatography (silica gel: 40 g, eluting solvent: heptane,heptane/ethyl acetate=90/10) to yield the title compound (350 mg, 1.91mmol, 54.8%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆)δppm; 2.03 (3H,s), 3.93 (3H, s), 8.02 (2H, br s), 8.11 (1H, s).

Test Example 1

<Inhibitory Effects on Gastric Acid Secretion in Rats>

Seven-week-old male SD rats fasted from the day before experiments wereused. The rats were subjected to celiotomy along the median line underether anesthesia, and the pylorus was ligated. Test compounds weredissolved or suspended in 0.5% methyl-cellulose solution (solvent) andprepared the concentration of 5 mg/ml. Histamine was dissolved in brine(solvent) and prepared the concentration of 10 mg/ml. 0.5%methyl-cellulose solution or test compound solution (10 mg/kg) in avolume of 0.2 ml per 100 g body weight was injected into the duodenum atthe time of ligation, and then histamine solution (20 mg/kg) in a volumeof 0.2 ml per 100 g body weight was administered subcutaneously. Thenthe abdomen was sutured.

Eight hours after the administration of solvent or test compound, ratwas sacrificed and stomach was isolated for the measurement of thevolume of gastric juice. After the volume of gastric juice wasdetermined, the acid concentration was measured using 0.25 ml of gastricjuice by titration against 0.04 mol/l NaOH solution to pH 7.0. The acidoutput was calculated as (volume of gastric juice)×(acid concentration).The inhibition rate (%) was calculated according to the formula shownbelow. The results are shown in Table 1. The number of animals of eachexperimental group is four.Inhibition rate(%)=100×(A−B)/A

-   A: acid output in solvent administered group

B: acid output in test compound administered group TABLE 1 CompoundInhibition rate(%) Example 1 79 Example 2 86 Example 3 85

Test Example 2

<Measurement of Cytochrome P450 (CYP) Gene Induction in HumanCryopreserved Hepatocytes>

Human cryopreserved hepatocytes purchased from In Vitro Technology werequickly thawed at 37° C. After ice-cold William's E (WE) mediumsupplemented with 10% FCS, penicillin (100U/mL), streptomycin (100μg/mL) and glutamine (2 mM) (WE medium) was gradually added tohepatocytes, the cells were centrifuged at 500 rpm for 5 min at 4° C.The supernatant was removed and the cells were resuspended in WE mediumto obtain 5×10⁵ cells/mL. The cells were plated into collagen-coated48-well plates (1×10⁵ cells/cm²) and cultured at 37° C. and 5% CO₂ forabout 24 hr.

Medium was replaced with Hepato-STIM (trademark, BD Biosciences)supplemented with EGF, penicillin (100U/mL), streptomycin (100 μg/mL)and glutamine (2 mM) (HS medium) and the cells were cultured for about24 hr. At about 48 hr of culture after seeding, the cells were treatedwith the test compounds and β-naphtoflavone (β-NF, positive control forhuman CYP1A1 and CYP1A2, SIGMA) prepared by HS medium for about 48 hr.Medium was changed daily. The final concentration of β-NF was set to 10μM. All compounds were dissolved in dimethylsulfoxide (DMSO, Wako),resulting in a final vehicle concentration of 0.1% (v/v). To the controlcells, HS medium containing 0.1% DMSO was added.

After 48-hr exposure, cells were washed once using PBS, and total RNAwas purified using Qiagen RNeasy Mini Kit (Qiagen) according to themanufacturer's instruction. Purified total RNA was then used as templatefor first strand cDNA synthesis. For reverse transcription (RT)reaction, Oligo dT was employed. The RT reaction was carried usingTaqMan Reverse Transcription Reagents (Applied Biosystems) at 25° C. for10 min followed by 60-min reaction at 48° C., and then the enzyme wasinactivated at 95° C. for 5 min in Gene Amp PCR System 9700. Theresulting cDNA was subjected to polymerase chain reaction (PCR) inABI7700 Sequence Detection System (Applied Biosystems). For the mRNAanalyses of CYP1A1 and GAPDH, SYBR Green PCR Core Reagents kit (AppliedBiosystems) was used, and CYP1A2 mRNA was quantified using TaqMan PCRCore Reagents kit (Applied Biosystems). The forward (F) and reverse (R)primers for the analysis of each mRNA and PCR conditions used were shownin Tables 2 and 3-5, respectively. TABLE 2 Primer Sequence isozymeGenBank # primer Name sequence CYP1A1 XM_044663 F hCYP1A1_F1TGGTCTOCGTTCTCTA CACTCTTGT R hCYP1A1_R1 ATTTTCCCTATTACAT TAAATCAATGGTTCTCYP1A2 AF_182274 F hCYP1A2_F12 ACCATGACCCAGAGC TGTGG R hCVP1A2_R13TCACTCAAGGGCTTGT TAAT Probe (FAM/ hCYP1A2_probel AGGACCCCTCTCAGTT TAMRA)CCGGCCT GAPDH M_33197 F hGAPDH_F GAAGGTGAAGGTCGG AGTC R hGAPDH_RGAAGATGGTGATGGG ATTTC

PCR Conditions TABLE 3 GAPDH Temperature Time 95 10 min 94 15 sdenaturation 56 15 s annealing 72 30 s extension 40 cycles

TABLE 4 CYP1A1 Temperature Time 95 10 min 94 15 s denaturation 56 15 sannealing 72 30 s extension 50 cycles

TABLE 5 CYP1A2 Temperature Time 95 10 min 94 15 s denaturation 58 15 sannealing 72 30 s extension 50 cycles<Data Analysis>

Data analysis was performed as follows. The amount of mRNA of CYP1A1 orCYP1A2 was divided by that of GAPDH. Then, the ratio (fold) of thevalues obtained in test compounds (X) and positive control (P) againstthat in control was calculated. The induction potency of test compound(%) was obtained by following equation:Induction potency of test compound(%)=100×(X−1)/(P−1)<Results>

In Test Example 2, to assess CYP induction in liver, which is one of theproblems in the development of new drug, induction of mRNAs of CYP1Aisozymes was studied using human cryopreserved hepatocytes. As theresults, test compound showed week induction potency, resulted in lessthan 12% at 3 uM and less than 30% at 10 uM as compared with positivecontrol (100%). TABLE 6 Sample Conc. CYP1A1 CYP1A2 Control 0.1% DMSO(1.00) (1.00) βNF  10 μM 100(79.97) 100(14.16) Example 1 0.3 μM 2.038.36 Example 1   1 μM 8.02 12.16 Example 1   3 μM 11.27 11.78 Example 1 10 μM 18.46 29.18

Each value in Table 6 represents the % of the positive control (100%).Figures in parentheses show the fold induction by positive control ascompared with control.

INDUSTRIAL APPLICABILITY

Since the compound of the present invention has an excellent gastricacid secretion inhibitory activity, higher safety and more suitablephysicochemical stability, it can serve as a drug particularly usefulfor acid related diseases.

SEQUENCE LISTING FREE TEXT

-   SEQ ID No. 1: Primer F-   SEQ ID No. 2: Primer R-   SEQ ID No. 3: Primer F-   SEQ ID No. 4: Primer R-   SEQ ID No. 5: Probe (FAM/TAMRA)-   SEQ ID No. 6: Primer F-   SEQ ID No. 7: Primer R

1. A compound represented by the following formula (1), or a saltthereof or a hydrate thereof: [Formula 1]

wherein R¹ represents a C1-C6 alkyl group which may have at least onesubstituent selected from the following α group, a C2-C6 alkenyl group,a C2-C6 alkynyl group, a C3-C6 cycloalkyl group, or a phenyl group whichmay have a substituent selected from the following β group; R²represents a hydrogen atom or a C1-C3 alkyl group; R³ represents amethyl or ethyl group; R⁴ represents a C1-C6 alkyl group; R⁵ representsa hydrogen atom; α group is a halogen atom, a C3-C6 cycloalkyl group, aphenyl group which may have at least one substituent selected from thefollowing β group or a phenyloxy group which may have a substituentselected from the following β group; β group is a halogen atom or aC1-C6 alkoxy group; provided that a compound wherein R¹ is a C1-C6 alkylgroup unsubstituted or substituted with a halogen atom and R² is ahydrogen atom is excluded.
 2. The compound or a salt thereof or ahydrate thereof according to claim 1, wherein R¹ is an unsubstitutedC1-C6 alkyl group.
 3. The compound or a salt thereof or a hydratethereof according to claim 1, wherein R¹ is a C2-C6 alkynyl group. 4.The compound or a salt thereof or a hydrate thereof of according toclaim 1, wherein R¹ is a C1-C6 alkyl group which may be substituted withhalogen.
 5. The compound or a salt thereof or a hydrate thereofaccording to claim 1, wherein R¹ is a phenyl group which may have asubstituent selected from the β group.
 6. The compound or a salt thereofor a hydrate thereof according to claim 1, wherein R¹ is a methyl group,2,2,2-trifluoroethyl group, 2,2-difluoroethyl group, 2-(phenyl)propylgroup, 2-(phenyloxy)ethyl group, 2-butynyl group, 3-fluorophenyl group,4-fluorophenyl group, or 4-methoxyphenyl group.
 7. The compound or asalt thereof or a hydrate thereof according to claim 1, wherein R¹ is amethyl group, 2,2,2-trifluoroethyl group or 2,2-difluoroethyl group. 8.The compound or a salt thereof or a hydrate thereof according to claim1, wherein R² is a hydrogen atom, methyl group, ethyl group or propylgroup.
 9. The compound or a salt thereof or a hydrate thereof accordingto claim 1, wherein R² is a methyl group.
 10. The compound or a saltthereof or a hydrate thereof according to claim 1, wherein R² is ahydrogen atom.
 11. The compound or a salt thereof or a hydrate thereofaccording to claim 1, wherein R³ is a methyl group.
 12. The compound ora salt thereof or a hydrate thereof according to claim 1, wherein R⁴ isa methyl group.
 13. The compound or a salt thereof or a hydrate thereofaccording to claim 1, said compound is selected from the groupconsisting of the following compounds:5-methoxy-2-(((4-methoxy-3-methyl-2-pyridinyl)methyl)sulfinyl)-6-methyl-3H-imidazo[4,5-b]pyridine,2-(((4-methoxy-3-methyl-2-pyridinyl)methyl)sulfinyl]-6-methyl-5-(2,2,2-trifluoroethoxy)-3H-imidazo[4,5-b]pyridine,and5-(2,2-difluoroethoxy)-2-(((4-methoxy-3-methyl-2-pyridinyl)methyl)sulfinyl)-6-methyl-3H-imidazo[4,5-b]pyridine.14. A pharmaceutical composition which comprises a compound or a saltthereof or a hydrate thereof according to claim 1, and apharmaceutically acceptable carrier.
 15. The pharmaceutical compositionaccording to claim 14, wherein the disease caused by gastric acid isgastric ulcer, duodenal ulcer, stomal ulcer, gastroesophageal refluxdisease, Zollinger-Ellison syndrome, symptomatic gastroesophageal refluxdisease, endoscopy-negative gastroesophageal reflux disease,gastroesophageal regurgitation, paresthesia of pharyngolarynx, Barrett'sesophagus, non-steroidal antiinflammatory drug (NSAID) ulcer, gastritis,stomach bleeding, gastrointestinal bleeding, peptic ulcer, bleedingulcer, stress ulcer, gastric hyperacidity, dyspepsia, gastroparesis,senile ulcer, intractable ulcer, heartburn, bruxism, stomachache, heavystomach, temporomandibular arthrosis or erosive gastritis.
 16. Thepharmaceutical composition according to claim 14, wherein the diseasecaused by gastric acid is gastric ulcer, duodenal ulcer, stomal ulcer,gastroesophageal reflux disease, Zollinger-Ellison syndrome orsymptomatic gastroesophageal reflux disease.
 17. The pharmaceuticalcomposition according to claim 14, wherein the disease caused by gastricacid is gastroesophageal reflux disease or symptomatic gastroesophagealreflux disease.
 18. The pharmaceutical composition according to claim14, wherein the disease caused by gastric acid is gastric ulcer orduodenal ulcer.
 19. A mono therapeutic or combination therapeutic agentfor eradication of Helicobacter Pylori in a stomach which comprises thecompound or a salt thereof or a hydrate thereof according to claim 1.